HOW SAFE IS GADOBUTROL? EXAMINING THE EFFECT OF GADOLINIUM DEPOSITION ON THE NERVOUS SYSTEM

Abstract

Background and objective: Repeated administration of Gadolinium based contrast agents (GBCAs) has been shown to cause Gadolinium (Gd) deposition in the nervous system. It is unclear whether neurotoxic effects can arise from this deposition. The aim of this study was to evaluate the safety of the GBCA, Gadobutrol, by assessing its effect on the central and peripheral nervous system under normal conditions and to investigate whether neuroinflammation can exacerbate the effect of Gadobutrol.

Methods: As such, 24 male Sprague Dawley rats were divided into 4 groups that consisted of a saline group, Gadobutrol group, lipopolysaccharide (LPS) + saline group and an LPS + Gadobutrol group. Gadobutrol and saline were administered intraperitoneally for 20 days at a dosage of 2.5mmol/kg while LPS was given intraperitoneally at a dosage of 5mg/kg followed by Gadobutrol or saline after 1 hour and for 20 days. Behavioral tests that include the heat hyperalgesia test, beam walking test, and spontaneous alternation T-maze test were conducted weekly over a period of 4 weeks to evaluate pain sensitivity, motor function, and cognitive ability. Gd concentration was measured in the brain and peripheral nerves, using Inductively Coupled Plasma Mass Spectrometry (ICP-MS), one week following the last set injection. Additionally, electromyography (EMG) and an assay of lactate dehydrogenase (LDH) activity in the sciatic nerve and hippocampus were carried out. One-way ANOVA followed by Tukey’s test in addition to multiple t-tests and unpaired t-tests were utilized for statistical analysis.

Results and conclusion: Results showed that Gadobutrol did not cause behavioral deficits under normal conditions; however, the cumulative effect of LPS and Gadobutrol significantly impaired pain sensitivity over time. ICP-MS showed Gd deposition in the cerebrum and peripheral nerves in addition to greater deposition in the cerebrum of the LPS + Gadobutrol group. LDH activity was significantly higher in the hippocampus of the Gadobutrol group but not in the sciatic nerve and EMG revealed that Gadobutrol led to a decreased activation threshold in the sciatic nerve. In conclusion, repeated administration of Gadobutrol is safe under normal conditions; however, inflammation can exacerbate the effect of Gadobutrol over time leading to central and peripheral manifestations.