# Cerebral Accumulation of Gadolinium (Gd3+) and Related Cellular Stress Pathways in Rat Brain Tissue

## TL;DR

This study compares how two types of MRI contrast agents affect Gd3+ accumulation and stress in rat brains, finding that macrocyclic agents are safer.

## Contribution

The study reveals distinct cerebral accumulation and stress profiles between linear and macrocyclic GBCAs in rats.

## Key findings

- Linear GBCAs caused persistent Gd3+ accumulation, while macrocyclic GBCAs showed a time-dependent decline.
- Linear GBCAs triggered elevated stress markers like PERK, DDIT3, and ATF6, unlike macrocyclic GBCAs.
- IRE-1, TAS, and TOS levels remained unchanged in both groups.

## Abstract

Cerebral gadolinium (Gd3+) accumulation, unfolded protein response level, and oxidative stress were studied in rat basal ganglia after exposure to gadopentetate dimeglumine (linear) and gadoterate meglumine (macrocyclic). Both agents resulted in Gd3+ accumulation in cerebral tissue at 24 and 72 h; however, it remained stable with the linear agent, while a time-dependent decline was observed with the macrocyclic agent. Elevated levels of PERK, DDIT3, and ATF6 were observed with the linear agent, in contrast to the macrocyclic agent, which did not reveal a significant stress response. In addition, IRE-1, TAS, and TOS remained significantly unchanged. Overall, the two agents showed different accumulation properties and cellular stress profile patterns, supporting the preferential use of macrocyclic GBCAs.

Background/Objectives: This study aimed to compare in vivo cerebral gadolinium (Gd3+) accumulation, associated unfolded protein response (UPR), and oxidative stress parameters in rats after exposure to gadolinium-based contrast agents (GBCAs). Methods: This study was designed as a controlled, experimental animal study to evaluate the accumulation of Gd3+ in the basal ganglia of rats following the administration of 0.6 mmol/kg gadopentetate dimeglumine (linear) and gadoterate meglumine (macrocyclic). Male Sprague–Dawley rats were exposed to the contrast agents for 24 and 72 h, and then the basal ganglia tissues were collected postmortem. The tissue levels of Gd3+ accumulation, activating transcription factor-6 (ATF6), inositol-requiring enzyme-1 (IRE-1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), damage-inducible transcript-3 (DDIT3), total antioxidant status (TAS), and total oxidant status (TOS) were determined. Results: Linear GBCA-treated rats had persistent Gd3+ levels over time, whereas a significant reduction from 24 to 72 h was observed in macrocyclic GBCA-treated rats (p < 0.001). PERK, DDIT3, and ATF6 expressions were significantly elevated after linear GBCA exposure (p < 0.05), while no significant increase was observed in the macrocyclic GBCA-treated group. However, IRE-1, TAS, and TOS levels were not significantly different in either group. Conclusions: Linear and macrocyclic GBCAs demonstrated distinct patterns of cerebral Gd3+ accumulation and UPR levels in rats. Accordingly, GBCA administration should be reserved for instances where it is necessary, such as when contrast enhancement is clinically required.