Experimental Study On The Deposition Of Gadolinium-based Contrast Agent And Its Enhanced The Expression Of NLRP3 Inflammasome Activation Mechanism In The Brain Of Type 2 Diabetic Rats

Gadolinium-based contrast agents(GBCAs)are widely used to diagnose and monitor disease progression in contrast-enhanced magnetic resonance imaging(CE-MRI).Over 30 million doses of GBCAs are used worldwide every year.Clinically available GBCAs are all bonded by a ligand when they are used as an MRI contrast agent,due to the free gadolinium is highly toxic.Until 2006,all GBCAs were considered extremely safe.In 2006,some GBCAs may cause nephrogenic systemic fibrosis(NSF)in patients with renal failure were reported.However,no new NSF case has been reported during the period when renal filtration rate was fully assessed prior to CE-MRI.Since 2013,the safety of GBCAs had attracted broad attentions over the world.A research group from Japan reported that signal intensity in the deep cerebellar nucleus(DCN)on unenhanced T1 weighted imaging(T1WI)may be a result of the previous GBCAs administrations.After that report,many studies focused on the potential risks of gadolinium retention in the human brain.We evaluated the effect of different types of GBCAs on the gadolinium deposition in brain.The possible entry and clearance mechanisms of gadolinium and the potential side effects of gadolinium deposition in the brain were described.Patients with type 2 diabetes mellitus(T2DM)often need multiple CE-MRI examinations,because they are always with many vascular diseases.The destruction of blood-brain barrier(BBB)affects the deposition of GBCAs in the brain,and type 2 diabetes mellitus is associated with BBB damage and renal insufficiency.Therefore,it is important to study gadolinium deposition in type 2 diabetes mellitus.NSF is a progressive fibrosing disorder that primarily affects individuals with chronic kidney disease following exposure to GBCAs administered for MRI and angiography.In vitro,GBCAs can induce peripheral blood monocytes and monocyte derived macrophages to produce cytokines,promote the activation of fibroblasts and increase the production of extracellular matrix components.NLRP3 is a part of a family of protein complexes,called inflammasome and plays an important role in innate immunity.After NLRP3 activated,it can interact with ASC adaptor proteins,to activate Caspase-1,interleukin(IL)-1β and IL-18.There is a great interest in the recent introduction of inflammation,a macromolecular platform composed of NLR(Nod)-like receptor proteins,ASC(proteins containing apoptosis-associated spotted CARD),and pro-caspase-1 proteins.Inflammation is responsible for the proteolytic processing of immature forms of interleukin-1β(IL-1β)and IL-18.The two potent pro-inflammatory cytokines are pleiotropic.At present,there was no research on type 2 diabetes and GBCAs in brain deposition and clearance.In type 2 diabetic patients,no correlation has been reported between gadolinium deposition in brain and inflammatory immunity.Here,we report that multiple injections of linear GBCAs including gadodiamide and gadopentetate dimeglumine can cause gadolinium deposition in the brain and high signal in T1 sequence,especially in DCN.In type 2 diabetes and normal rats,gadolinium deposition of linear contrast agent was significantly higher than that of macrocyclic contrast agents,and gadodiamide was the most.In each group,Olfactory bulb and DCN were the places with the largest amount of gadolinium deposition.After injection of GBCAs in type 2 diabetic rats,the deposition of gadolinium contrast agent in the brain was much higher than that in the normal rats.The clearance of GBCAs in the brain was influenced by type 2 diabetes,and the clearance of GBCAs in the brain was inhibited in type 2 diabetes.In type 2 diabetic rats,gadolinium deposition can cause behavioral changes,and mediate neuroinflammation by enhancing the NLRP3-Caspase-1-IL-1β pathway.Gadodiamide can enhance the activation of microglia and invasiveness,stimulate the transformation of microglia into type M1,increase the apoptosis of neuronal apoptosis and decrease the membrane potential of mitochondrial.Together,our results first identify that gadolinium deposition occurred in the brain of type 2 diabetic rats after multiple injections of GBCAs through inductively coupled plasma mass spectrometry(ICP-MS),9.4 T magnetic resonance and transmission electron microscopy(TEM).Quantitative studies of gadolinium deposition in different brain regions were also performed.With the help of ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS)technology,the specific deposition form of GBCAs in the brain was studied for the first time in the rat model of type 2 diabetes.The mechanisms of GBCAs enter and deposit into the brain and the potential long-term biological and clinical implications require further research.In clinical practice,the assessment should be individualized and the potential unknown risk of deposition gadolinium should be considered before using GBCAs.It is recommended that macrocyclic GBCAs can be used at the lowest dose to reduce the deposition of gadolinium in the brain.The effect of GBCAs on the central nervous system after deposition in the brain is a research hotspot at this stage and even in the future,and further research is needed to better guide the standard application of GBCAs in clinical practice.At the same time,this study also provides new ideas for the development of new and safe MRI contrast agents.