Effects of Gadolinium Retention in the Brains of Type 2 Diabetic Rats after Repeated Administration of Gadolinium-Based MRI Contrast Agents on Neurobiology and NLRP3 Inflammasome Activation

Background: The neurotoxic potential of gadolinium (Gd)-based contrast agents (GBCAs) retention in the brains of patients with type 2 diabetes mellitus (T2DM) is unclear. Purpose: To determine the deposition and clearance of GBCAs in T2DM rats and the mechanism by which Gd enhances nucleotide-binding oligomerization domain-3 (NLRP3) inflammasome activation. Study Type: Cross-sectional, prospective. Animal Model: 104 T2DM male Wistar rats. Field Strength/Sequence: 9.4-T, T1-weighted fast spin echo sequence. Assessment: T2DM (male Wistar rats, n = 52) and control group (healthy, male Wistar rats, n = 52) rats received saline, gadodiamide, Gd-diethylenetriaminepentaacetic acid, and gadoterate meglumine for four consecutive days per week for 7 weeks. The distribution and clearance of Gd in the certain brain were assessed by MRI (T1 signal intensity and relaxation rate R1, on the last day of each week), inductively coupled plasma mass-spectroscopy, ultraperformance liquid chromatography mass spectrometry, and transmission electron microscopy. Behavioral tests, histopathological features, and the effects of GBCAs on neuroinflammation were also analyzed. Statistical Tests: One-way analysis of variance, bonferroni method, and unpaired t-test. A P-value <0.05 was considered statistically significant. Results: The movement distance and appearance time in the open field test of the T2DM rats in the gadodiamide group were significantly shorter than in the other groups. Furthermore, the expression of NLRP3, Pro-Caspase-1, interleukin-1 beta (IL-1 beta), and apoptosis-associated speck-like protein containing a CARD protein in neurons was significantly higher in the gadodiamide group than in the saline group, as shown by Western blot. Gadodiamide also induced differentiation of microglia into M1 type, decreased the neuronal mitochondrial membrane potential, and significantly increased neuronal apoptosis from flow cytometry. Data Conclusion: T2DM may affect both the deposition and clearance of GBCAs in the brain. Informed by the T2DM model, gadodiamide could mediate the neuroinflammatory response by NLRP3 inflammasome activation. Level of Evidence: 1 Technical Efficacy: Stage 1