Comprehensive phenotyping revealed transient startle response reduction and histopathological gadolinium localization to perineuronal nets after gadodiamide administration in rats

Abstract

Gadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.

Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

“…Although not directly comparable due to the use of adult mice and not offspring, this comprehensive study is in contrast to Khairinisa et al (2017), which showed some effects in an open field test, rotarod and object recognition (Khairinisa et al 2018 ). It also supports the many other studies which have looked at the potential effect of GBCA administration behaviour (Bussi et al 2018b ; Fretellier et al 2019 ; Alkhunizi et al 2020 ; Habermeyer et al 2020 ).…”

“…This highlights the potential sex differences but also that gadolinium concentration does not correlate to behavioural changes after supraclinical GBCA administration in mice. Other studies have shown no effect with linear agents on open field or rotarod tests, using similar dosing regiments in rats (Bussi et al 2018b ; Habermeyer et al 2020 ).…”

“…Conversely, females spent less time travelling but only spent less time in the centre zone in one, 10-min time bin. Although increased grooming behaviour is known to impact performance in open field tests, the authors did not comment on skin lesions or the grooming which may be resultant (Habermeyer et al 2020 ). Motor coordination as measured by the rotarod test showed both male groups of GBCAs differed from the control but were very similar to each other even though the gadodiamide group had 71 times more gadolinium in the brain compared with gadoterate.…”

“…No gadolinium was detected in the cochlear root nucleus, but the primary startle pathway consists of the auditory nerve; however, no hearing deficits were observed. The authors noted that gadodiamide-treated animals exhibited more grooming behaviour in the open field test, associated with skin lesions and they found no effect on neuronal numbers or pathway deregulation, suggesting no observable brain toxicity (Habermeyer et al 2020 ). Whilst these behavioural findings are important to consider, it must be noted that these are performed using supraclinical doses of GBCAs and there has been no preclinical evidence of chronic toxicity or histopathological changes in the brain in vivo as a result of gadolinium retained in the brain after GBCA administration (Lohrke et al 2017 ; McDonald et al 2017b ; Smith et al 2017 ).…”

In VitroToxicological Assessment of Gadodiamide in Normal Brain SVG P12 Cells

“…TFDA officially announced GBCAs could be applied for clinical use because there were no data to show that the accumulation of GBCAs could cause harm the brain on November 23, 2017. TFDA also declared that physicians should carefully evaluated GBCAs before use on a basis of clinical benefits (17), and suggested to use the lowest effective dose (18,19). The main purpose of the present study was to explore the mechanisms of damage and death of normal brain cells caused by the accumulation of high in vivo 35: 2621-2630 (2021)…”