Habermeyer, Johanna
[Verfasser:in]
;
von Hörsten, Stephan
[Akademische:r Betreuer:in];
von Hörsten, Stephan
[Sonstige Person, Familie und Körperschaft]
Drug monitoring of Gadolinium-based MRI contrast agents in rats: neurobehavioral, histological, and biochemical findings
Beschreibung:
Gadolinium-based contrast agents (GBCAs) are widely used in clinical magnetic resonance imaging (MRI) since the mid-1980s. Recently, concerns have been raised since abnormal signal increases on magnetic resonance images as well as trace amounts of gadolinium (Gd) were detected in the brain even years after GBCA application. The genesis, form of the retained Gd, and reversibility of this accumulation of Gd within the deep cerebellar nuclei and the Globus pallidus (GP) of the central nervous system (CNS) are still not fully explained. Especially clinically relevant consequences and potential comorbidity of the phenomenon are of greatest interest to assess the safety of the routinely used compounds. The American Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA) prompted all manufacturers of GBCAs as well as the scientific community to thoroughly investigate the phenomenon and to conduct vigilance studies. Following this official call, we assessed intermediate and long-term (5 – 52 weeks after the last injection) effects of multiple administrations of macrocyclic- (gadobutrol) and linear-chelated (gadodiamide) GBCAs in a rat model and studied neuro-histopathology as well as gene expression, and distribution of retained Gd in combination with a comprehensive behavioral phenotyping. As an established preclinical model, healthy male Wistar-Han rats received either 8 injections of 0.6, 1.2 or 1.8 mmol/kg BW gadobutrol, gadodiamide or saline as a control. Using a hypothesis-free study design, a broad range of behavioral domains including general health and metabolic status, motor function, emotion, sensorimotor function, nociception and cognition were investigated longitudinally for up to 52 weeks post GBCA administration (p.i.). Tissue samples were taken 11, 35 and 54 weeks p.i. for further assessment of the neuropathology. Mirroring the clinical situation, laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) revealed retention of Gd in the Nucleus dentatus (DN) of ...