Consequences of Gadolinium based contrast agents on the small fibers of the skin – combined in vivo and in vitro investigations in a rodent model

• Applicants: Professorin Dr. Astrid Jeibmann; Professor Dr. Christoph van Thriel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Nuclear Medicine, Radiotherapy, Radiobiology ; Toxicology, Laboratory Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505206189

Gadolinium based contrast agents (GBCAs) are indispensable tools in MRI examinations required for optimal diagnostics and therapeutic decision making. However, ionic Gd3+ is highly toxic and chelators are used for GBCAs to prevent or reduce the release of Gadolinium into the organism. Macrocyclic GBCAs enclose Gd3+ completely, while Gadolinium is only partially surrounded by the backbone of linear contrast agents. Both, macrocyclic and linear GBCAs are approved for medical use but recent studies raised concerns that regardless of the chelators GBCAs can cause toxic side effects to various organs. Our recent in vivo study showed that macrocyclic and linear GBCAs release Gd3+ into the skin of the treated mice, this release was stronger for linear than macrocyclic GBCAs, and peripheral nerve fibers showed neuropathological changes indicating degeneration or at least abnormal morphology. Again, linear GBCAs were more potent than macrocyclic GBCAs. These findings are in line with clinical observations from patients describing symptoms such as burning skin pain, typically in the lower arms and lower legs. The underlying condition might be small fiber neuropathy (SFN), a heterogeneous group of disorders affecting thinly myelinated Aδ- and unmyelinated C-fibers. Based on the clinical observations and the results of our study the proposed research project will examine the possible peripheral neurotoxicity of GBCAs in four inter-linked in vivo and in vitro work packages (WPs) in mice assessing: • Dose dependency of tissue accumulation and neurotoxicity after multiple injections (WP1) • possible reversibility after different recovery periods (WP2) • the behavioral phenotype related to SFN (WP3) • molecular and cellular mechanisms underlying the uptake and toxicity in neurons cultivated from mice dorsal root ganglia (WP4) with a focus on the role of TRP-channels. In all experiments the two GBCAs gadodiamide and gadoterate-meglumine will be used to investigate the impact of macrocyclic vs. linear chelation. In both cases the dosing regimen of WP1 will be comparable to treatment of patients and the results of WP1 will inform the other WPs about relevant but neurotoxic doses. The in vivo experiments in WP 2 and 3 will shed light on the question if the neurotoxic side effects are comparable with the neuropathological features of SFN. Finally, the cell-based experiments will provide mechanistic insights that could be used as targets (e.g. TRP-channels) for pharmacological treatment of possible side effects. The expected results will provide a better scientific knowledge about the safe use of GBCAs in clinical applications and the avoidance of neurotoxic side effects by recommending the least toxic GBCA, doses that yield reversible effects and candidates that will reduce the clinical symptoms during the treatment period.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Co-Investigator: Professor Dr. Alexander Radbruch
• Cooperation Partner: Henning Richter, Ph.D.