The regional distribution of manganese in the normal human brain

Bonilla, Ernesto; Salazar, Enrique Gonzalo Rojas; Villasmil, J.; Villalobos, Rafael

doi:10.1007/bf00965060

Cited by 35 publications

(11 citation statements)

References 12 publications

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“…Fixed sections of marmoset brain were slightly higher in Zn and Mn than rodent or ovine species, and Fe level in the marmoset were comparable to those reported in rats and mice, especially in high-Fe regions such as the substantia nigra and basal ganglia. One notable feature of this study was the disparity between observed Mn concentrations and levels reported for human autopsy specimens, 38 which contained approximately 10 times as much Mn as the postmortem marmoset brain (Table 4).…”

Section: Comparison Of Metal Levels Across Speciesmentioning

confidence: 71%

Whole-brain metallomic analysis of the common marmoset (Callithrix jacchus)

et al. 2017

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Despite the importance of transition metals for normal brain function, relatively little is known about the distribution of these elemental species across the different tissue compartments of the primate brain. In this study, we employed laser ablation-inductively coupled plasma-mass spectrometry on PFA-fixed brain sections obtained from two adult common marmosets. Concurrent cytoarchitectonic, myeloarchitectonic, and chemoarchitectonic measurements allowed for identification of the major neocortical, archaecortical, and subcortical divisions of the brain, and precise localisation of iron, manganese, and zinc concentrations within each division. Major findings across tissue compartments included: (1) differentiation of white matter tracts from grey matter based on manganese and zinc distribution; (2) high iron concentrations in the basal ganglia, cortex, and substantia nigra; (3) co-localization of high concentrations of iron and manganese in the primary sensory areas of the cerebral cortex; and (4) high manganese in the hippocampus. The marmoset has become a model species of choice for connectomic, aging, and transgenic studies in primates, and the application of metallomics to these disciplines has the potential to yield high translational and basic science value.

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Section: Comparison Of Metal Levels Across Speciesmentioning

confidence: 71%

Whole-brain metallomic analysis of the common marmoset (Callithrix jacchus)

et al. 2017

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“…The olfactory bulb is another brain area that accumulates Mn (Donaldson et al, 1973; Bonilla et al, 1982). Metal workers exposed to welding fumes have olfactory dysfunction, and Parkinson’s disease patients also display similar loss of function (Antunes et al, 2007; Doty, 2012).…”

Section: Discussionmentioning

confidence: 99%

Iron depletion increases manganese uptake and potentiates apoptosis through ER stress

Seo

Wessling‐Resnick

2013

NeuroToxicology

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Iron deficiency is a risk factor for manganese (Mn) accumulation. Excess Mn promotes neurotoxicity but the mechanisms involved and whether iron depletion might affect these pathways is unknown. To study Mn intoxication in vivo, iron deficient and control rats were intranasally instilled with 60 mg MnCl2/kg over 3 weeks. TUNEL staining of olfactory tissue revealed that Mn exposure induced apoptosis and that iron deficiency potentiated this effect. In vitro studies using the dopaminergic SH-SY5Y cell line confirmed that Mn-induced apoptosis was enhanced by iron depletion using the iron chelator desferrioxamine. Mn has been reported to induce apoptosis through endoplasmic reticulum stress. In SH-SY5Y cells, Mn exposure induced the ER stress genes glucose regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP). Increased phosphorylation of the eukaryotic translation initiation factor 2α (phospho-eIF2α) was also observed. These effects were accompanied by the activation of ER resident enzyme caspase-12, and the downstream apoptotic effector caspase-3 was also activated. All of the Mn-induced responses were enhanced by DFO treatment. Inhibitors of ER stress and caspases significantly blocked Mn-induced apoptosis and its potentiation by DFO, indicating that ER stress and subsequent caspase activation underlie cell death. Taken together, these data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency most likely through upregulation of DMT1.

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“…Purified microglia were seeded onto six-well tissue culture plates at a density of 3 × 10 5 cells/well and treated with saline (equal volume as treated, 1 μL/mL), to account for changes in osmolarity when treating cells with MnCl 2 , or MnCl 2 at 10, 30, or 100 μM from 2 to 24 h. Doses of MnCl 2 were chosen to range from normal to three to five times physiological levels based on previous research indicating that oral exposure in humans and rodents can result in upwards of two to six fold normal physiological concentrations (normal ranges between 10 and 30 μM) [31–34]. Astrocytes were seeded and treated as described below.…”

Section: Methodsmentioning

confidence: 99%

Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity

Kirkley¹,

Popichak²,

Afzali³

et al. 2017

J Neuroinflammation

260

184

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BackgroundAs the primary immune response cell in the central nervous system, microglia constantly monitor the microenvironment and respond rapidly to stress, infection, and injury, making them important modulators of neuroinflammatory responses. In diseases such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and human immunodeficiency virus-induced dementia, activation of microglia precedes astrogliosis and overt neuronal loss. Although microgliosis is implicated in manganese (Mn) neurotoxicity, the role of microglia and glial crosstalk in Mn-induced neurodegeneration is poorly understood.MethodsExperiments utilized immunopurified murine microglia and astrocytes using column-free magnetic separation. The effect of Mn on microglia was investigated using gene expression analysis, Mn uptake measurements, protein production, and changes in morphology. Additionally, gene expression analysis was used to determine the effect Mn-treated microglia had on inflammatory responses in Mn-exposed astrocytes.ResultsImmunofluorescence and flow cytometric analysis of immunopurified microglia and astrocytes indicated cultures were 97 and 90% pure, respectively. Mn treatment in microglia resulted in a dose-dependent increase in pro-inflammatory gene expression, transition to a mixed M1/M2 phenotype, and a de-ramified morphology. Conditioned media from Mn-exposed microglia (MCM) dramatically enhanced expression of mRNA for Tnf, Il-1β, Il-6, Ccl2, and Ccl5 in astrocytes, as did exposure to Mn in the presence of co-cultured microglia. MCM had increased levels of cytokines and chemokines including IL-6, TNF, CCL2, and CCL5. Pharmacological inhibition of NF-κB in microglia using Bay 11-7082 completely blocked microglial-induced astrocyte activation, whereas siRNA knockdown of Tnf in primary microglia only partially inhibited neuroinflammatory responses in astrocytes.ConclusionsThese results provide evidence that NF-κB signaling in microglia plays an essential role in inflammatory responses in Mn toxicity by regulating cytokines and chemokines that amplify the activation of astrocytes.

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The regional distribution of manganese in the normal human brain

Cited by 35 publications

References 12 publications

Whole-brain metallomic analysis of the common marmoset (Callithrix jacchus)

Whole-brain metallomic analysis of the common marmoset (Callithrix jacchus)

Iron depletion increases manganese uptake and potentiates apoptosis through ER stress

Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity

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