Iron Homeostasis in the CNS: An Overview of the Pathological Consequences of Iron Metabolism Disruption

Porras, Christina Ann-Marie; Rouault, Tracey A.

doi:10.3390/ijms23094490

Cited by 22 publications

(9 citation statements)

References 113 publications

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“…The concentrations of free zinc are therefore controlled by zinc transporters 15 , metallothioneins 16 and possibly other zinc proteins 17 . Other homeostatic mechanisms control the concentration of "free" copper, which is now also recognized as a signalling molecule 18 , and iron [19][20][21] . Zinc has been implicated in pathophysiological processes underlying brain diseases such as epilepsy 22 , ischemic stroke [23][24][25][26] , traumatic brain injury [27][28][29] , Alzheimer's 30,31 and Parkinson's disease 32 , neuropsychiatric conditions such as major depression 33 and schizophrenia 34 , and neurodevelopmental disorders including autism spectrum disorders 35,36 .…”

Section: Background and Summarymentioning

confidence: 99%

A Timm-Nissl multiplane microscopic atlas of rat brain zincergic terminal fields and metal-containing glia

et al. 2023

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The ability of Timm’s sulphide silver method to stain zincergic terminal fields has made it a useful neuromorphological marker. Beyond its roles in zinc-signalling and neuromodulation, zinc is involved in the pathophysiology of ischemic stroke, epilepsy, degenerative diseases and neuropsychiatric conditions. In addition to visualising zincergic terminal fields, the method also labels transition metals in neuronal perikarya and glial cells. To provide a benchmark reference for planning and interpretation of experimental investigations of zinc-related phenomena in rat brains, we have established a comprehensive repository of serial microscopic images from a historical collection of coronally, horizontally and sagittally oriented rat brain sections stained with Timm’s method. Adjacent Nissl-stained sections showing cytoarchitecture, and customised atlas overlays from a three-dimensional rat brain reference atlas registered to each section image are included for spatial reference and guiding identification of anatomical boundaries. The Timm-Nissl atlas, available from EBRAINS, enables experimental researchers to navigate normal rat brain material in three planes and investigate the spatial distribution and density of zincergic terminal fields across the entire brain.

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Section: Background and Summarymentioning

confidence: 99%

A Timm-Nissl multiplane microscopic atlas of rat brain zincergic terminal fields and metal-containing glia

et al. 2023

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“…The very first regions identified to contain Gd after linear GBCA administration-DCN, GP, and striatum-have long been recognized to be rich in Fe. [28][29][30] In the face of the pronounced Gd presence in Fe-rich brain structures, the notion of transmetalation as a major contributor to Gd accumulation in the CNS seemed quite plausible. 12,23,27 Reports on Gd-Fe colocalizations as derived from visual inspections of juxtaposed or overlaid element maps obtained by LA-ICP-MS seem to support this notion.…”

Section: Colocalization Of Gadolinium With Iron Manganese and Endothe...mentioning

confidence: 99%

“…12,23,27 The deep cerebellar nuclei (DCN), GP, and striatum, that is, the first structures in which residual Gd was detected, are known to be rich in iron (Fe). [28][29][30] By means of juxtaposed or overlaid element maps obtained by LA-ICP-MS, colocalizations of Gd and Fe have been observed. 21,[23][24][25] Thus, transmetalation has been proposed as a major reason behind the spatial patterns of residual Gd.…”

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confidence: 99%

“…This process of transmetalation could occur in tissues with high levels of endogenous metals 12,23,27 . The deep cerebellar nuclei (DCN), GP, and striatum, that is, the first structures in which residual Gd was detected, are known to be rich in iron (Fe) 28–30 . By means of juxtaposed or overlaid element maps obtained by LA-ICP-MS, colocalizations of Gd and Fe have been observed 21,23–25 .…”

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confidence: 99%

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Comprehensive Analysis of the Spatial Distribution of Gadolinium, Iron, Manganese, and Phosphorus in the Brain of Healthy Rats After High-Dose Administrations of Gadodiamide and Gadobutrol

Hummel,

Frenzel,

Boyken

et al. 2023

Invest Radiol

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Objectives After the administration of gadolinium-based contrast agents (GBCAs), residual gadolinium (Gd) has been detected in a few distinct morphological structures of the central nervous system (CNS). However, a systematic, comprehensive, and quantitative analysis of the spatial Gd distribution in the entire brain is not yet available. The first aim of this study is to provide this analysis in healthy rats after administration of high GBCA doses. The second aim is to assess the spatial distributions and possible Gd colocalizations of endogenous iron (Fe), manganese (Mn), and phosphorus (P). In addition, the presence of Gd in proximity to blood vessels was assessed by immunohistochemistry. Materials and Methods Male rats were randomly assigned to 3 groups (n = 3/group): saline (control), gadodiamide (linear GBCA), and gadobutrol (macrocyclic GBCA) with cumulative Gd doses of 14.4 mmol/kg of body mass. Five weeks after the last administration, the brains were collected and cryosectioned. The spatial distributions of Gd, Fe, Mn, and P were analyzed in a total of 130 sections, each covering the brain in 1 of the 3 perpendicular anatomical orientations, using laser ablation coupled with inductively coupled plasma mass spectrometry. Quantitative spatial element maps were generated, and the concentrations of Gd, Fe, and Mn were measured in 31 regions of interest covering various distinct CNS structures. Correlation analyses were performed to test for possible colocalization of Gd, Fe, and Mn. The spatial proximity of Gd and blood vessels was studied using metal-tagged antibodies against von Willebrand factor with laser ablation coupled with inductively coupled plasma mass spectrometry. Results After administration of linear gadodiamide, high Gd concentrations were measured in many distinct structures of the gray matter. This involved structures previously reported to retain Gd after linear GBCA, such as the deep cerebellar nuclei or the globus pallidus, but also structures that had not been reported so far including the dorsal subiculum, the retrosplenial cortex, the superior olivary complex, and the inferior colliculus. The analysis in all 3 orientations allowed the localization of Gd in specific subregions and layers of certain structures, such as the hippocampus and the primary somatosensory cortex. After macrocyclic gadobutrol, the Gd tissue concentration was significantly lower than after gadodiamide. Correlation analyses of region of interest concentrations of Gd, Fe, and Mn revealed no significant colocalization of Gd with endogenous Fe or Mn in rats exposed to either GBCA. Immunohistochemistry revealed a colocalization of Gd traces with vascular endothelium in the deep cerebellar nuclei after gadobutrol, whereas the majority of Gd was found outside the vasculature after gadodiamide. Conclusions In rats exposed to gadodiamide but not in rats exposed to gadobutrol, high Gd concentrations were measured in various distinct CNS structures, and structures not previously reported were identified to contain Gd, including specific subregions and layers with different cytoarchitecture and function. Knowledge of these distinct spatial patterns may pave the way for tailored functional neurological testing. Signs for the localization of the remaining Gd in the vascular endothelium were prominent for gadobutrol but not gadodiamide. The results also indicate that local transmetalation with endogenous Fe or Mn is unlikely to explain the spatial patterns of Gd deposition in the brain, which argues against a general role of these metals in local transmetalation and release of Gd ions in the CNS.

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“…Therapeutic approaches to minimize the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds, and iron chelation. Porras and Rouault [ 9 ] presented an overview of the pathological consequences of iron metabolism disruption in CNS, which has increasingly been implicated in various neurological disorders. This review examined the consequences of both iron accumulation and deficiency in various disease contexts, including neurodegenerative, neurodevelopmental, and neuropsychological disorders.…”

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confidence: 99%

New Advances in Iron Metabolism, Ferritin and Hepcidin Research

Arosio

2022

IJMS

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Iron Homeostasis in the CNS: An Overview of the Pathological Consequences of Iron Metabolism Disruption

Cited by 22 publications

References 113 publications

A Timm-Nissl multiplane microscopic atlas of rat brain zincergic terminal fields and metal-containing glia

A Timm-Nissl multiplane microscopic atlas of rat brain zincergic terminal fields and metal-containing glia

Comprehensive Analysis of the Spatial Distribution of Gadolinium, Iron, Manganese, and Phosphorus in the Brain of Healthy Rats After High-Dose Administrations of Gadodiamide and Gadobutrol

New Advances in Iron Metabolism, Ferritin and Hepcidin Research

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