ABSTRACT
Gadolinium deposition in the brain has been observed in areas rich in iron, such as the dentate nucleus of the cerebellum. We investigated the role of Fe2+ in the effect of gadolinium-based contrast agents (GBCA) on thyroid hormone-mediated Purkinje cell dendritogenesis in a cerebellar primary culture. The study comprises the control group, Fe2+ group, GBCA groups (gadopentetate group or gadobutrol group), and GBCA+Fe2+ groups. Immunocytochemistry was performed with an anti-calbindin-28K (anti-CaBP28k) antibody, and the nucleus was stained with 4',6-diamidino-2-phenylindole (DAPI). The number of Purkinje cells and their arborization were evaluated with an analysis of variance with a post-hoc test. The number of Purkinje cells was similar to the control groups among all treated groups. There were no significant differences in dendrite arborization between the Fe2+ group and the control groups. The dendrite arborization was augmented in the gadopentetate and the gadobutrol groups when compared to the control group (p < 0.01, respectively). Fe2+ significantly increased the effect of gadopentetate on dendrite arborization (p < 0.01) but did not increase the effect of gadobutrol. These findings suggested that the chelate thermodynamic stability and Fe2+ may play important roles in attenuating the effect of GBCAs on the thyroid hormone-mediated dendritogenesis of Purkinje cells in in vitro settings.
ABSTRACT
OBJECTIVE: To investigate the role of transporter proteins in gadolinium (Gd) distribution and retention in the brain after one high-dose injection of Gd-based contrast agent (GBCA). METHODS AND MATERIALS: 30 ddY mice were randomly divided into three treatment groups to be intravenously injected with either Gadodiamide (linear GBCA), Gadobutrol (macrocyclic GBCA), or Gadoterate (macrocyclic GBCA) at a dose of 5 mmol/kg, while five mice in the control group received 250 µL saline. Five minutes (5 min) and ten days (10d) post-injection, the cerebrospinal fluid (CSF), choroid plexus (CP), and meninges and associated vasculature (MAV) were collected. The brain was then dissected to obtain the olfactory bulb, cerebral cortex, hippocampus, cerebellum, and brainstem. Proteins were extracted and separated by a size-exclusion high-performance liquid chromatography (SEC) system, and Gd concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: 5 m post-injection, the Gadodiamide group had the highest Gd concentration, while Gadoterate had the lowest Gd concentration in all parts of the brain (p < .05). Gd concentration was highest in the cerebrospinal fluid (CSF) of the Gadodiamide group (578.4 ± 135.3 nmol), while Gd concentration was highest in MAV in the Gadobutrol group (379.7 ± 75.4 nmol) at 5 min post-injection. At 10d, in spite of the significant decrease of Gd from all GBCAs ( p < 0.01), retained Gd from Gadodiamide was detected all over the brain in several molecules that varied in size. Gd from Gadobutrol detected in the olfactory bulb (8.7 ± 4.5 nmol) was significantly higher than in other parts of the brain. Although most Gd from Gadobutrol was found in molecules similar in size to Gadobutrol, it was also found in several protein molecules of molecular size larger than the contrast agents. Only a small amount of Gd from Gadoterate was found in the brain. CONCLUSION: GBCAs may be able to pass through intact brain barriers, and the chemical structures of GBCAs may affect the penetration capability of Gd into the brain. Retained Gd in the brain tissue from Gadodiamide and Gadobutrol may be bound to some organic molecules, including proteins. ADVANCES IN KNOWLEDGE: Intact GBCA are able to penetrate a series of brain barrier immediately after administration regardless the type of the chelate. Gd may be bound with macromolecules that may cause Gd retention in the brain.
