EPR-based Assessment of Gadolinium-based Contrast Agent Retention and Gadolinium Transchelation in Inflamed Murine...

Area of Science:

• Neuroimaging and Contrast Agents
• Biophysical Chemistry
• Neuroinflammation Research

Background:

• Repeated administration of linear gadolinium-based contrast agents (GBCAs) is linked to increased cerebellar gadolinium (Gd) retention, particularly under neuroinflammatory conditions.
• Understanding the chemical state and location of retained Gd within the central nervous system (CNS) is crucial for assessing potential long-term effects.

Purpose of the Study:

• To differentiate between Gd retained within the GBCA complex and free Gd dissociated from the complex in the CNS.
• To characterize the molecular environment of released Gd³⁺ ions within intact brain tissue.
• To investigate the impact of neuroinflammation on Gd retention and speciation.

Main Methods:

• Electron paramagnetic resonance (EPR) and electron-nuclear double resonance (ENDOR) spectroscopy were employed on cerebellar biopsies and organotypic hippocampal slice cultures.
• Experiments were conducted both in vivo using a murine multiple sclerosis model and ex vivo under inflammatory conditions.
• Complementary mass spectrometry (MS) and MRI calibration experiments were performed on homogenized brain tissue.

Main Results:

• EPR successfully detected Gd levels in the µM range in intact cerebellar tissue, distinguishing between complex-bound and released Gd after linear GBCA administration.
• ENDOR revealed the presence of phosphorus-containing molecules in the microenvironment of released Gd in biopsies.
• MS and MRI calibration experiments indicated binding of released Gd to inorganic ligands in homogenized brain tissue.

Conclusions:

• EPR and ENDOR are sensitive techniques for detecting Gd³⁺ release and characterizing retained Gd species in intact brain tissue.
• The study demonstrates that neuroinflammation promotes Gd retention.
• Integrating in vivo and ex vivo analyses is essential for understanding long-term Gd retention mechanisms, and conventional MRI may underestimate Gd accumulation, especially in neuroinflammatory states.