The impact of manganese on neurotransmitter systems

Soares, Ana Thalita Gonçalves; Silva, Aline de Castro; Tinkov, Alexey A.; Khan, Haroon; Santamarı́a, Abel; Skalnaya, Margarita G.; Skalny, Anatoly V.; Tsatsakis, Aristidis; Bowman, Aaron B.; Aschner, Michael; Ávila, Daiana Silva

doi:10.1016/j.jtemb.2020.126554

Cited by 39 publications

(31 citation statements)

References 122 publications

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“…Taken together, these mechanisms may underlie Mn-induced alterations of neurotransmitter release. At the same time, recent studies have also unraveled the interference between Mn exposure and neurotransmitter metabolism [ 28 ].…”

Section: Neurotransmissionmentioning

confidence: 99%

“…In view of the significant neurological effects of Mn exposure, the mechanisms of Mn-induced neurotoxicity have been extensively studied. Key mechanisms include neuroinflammation, impaired calcium homeostasis [ 24 ], dysregulation of mitochondrial function and redox homeostasis [ 25 ], altered proteostasis [ 26 ], impaired microRNAs (miRNA) function [ 27 ], and altered neurotransmitter metabolism [ 28 ], to name a few. Additionally, reports suggest that Mn homeostasis is affected by low dose cadmium feeding [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

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Section: Neurotransmissionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Tinkov

Paoliello

Mazilina

et al. 2021

IJMS

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“…We also report that in BMEC cultures, Co and Mn in conjunction with each of the three organic compounds were significantly more toxic than the corresponding organic compound alone. Mn neurotoxicity has been well studied [53][54][55]. In fact, using RBE cells, a rat brain endothelial cell line, dos Santos and colleagues showed that Mn demonstrated significant toxicity in a dose range of 200-800 µM and concluded that Mn induced mitochondrial injury in these cells [56].…”

Section: Discussionmentioning

confidence: 99%

Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts

Hoffman

Kalinich

2020

IJERPH

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Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl-m-toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium.

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“…High Mn accumulation can also lead to hepatic, cardiac, male reproductive disorders and nephrotoxicity. [77] In addition, the mechanism of Mn-induced oxidative stress may be due to the generation of hydroxyl radical species via Fentonlike reactions. [18] Finally, the liver is the primary organ to regulate the level of Mn in the body.…”

Section: Biological Effectsmentioning

confidence: 99%

Construction of Smart Manganese Dioxide‐Based All‐in‐One Nanoplatform for Cancer Diagnosis and Therapy

et al. 2020

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Manganese dioxide (MnO 2)-based functional nanomaterials have attracted great attention in the fields of nanoscience, biosensors, bioimaging, drug/ gene delivery, and cancer therapy. Especially, all-in-one tumor microenvironment (TME) responsive MnO 2-based nanoagents have become a research hotspot due to their simple fabrication procedure, high specific surface area, controllable size and morphologies, easy surface modification, TME response, and oxygen generation. This review aims to provide a comprehensive overview of strategies for construction of MnO 2-based all-in-one nanoplatforms for cancer diagnosis and therapy. Major highlighted topics in this paper focus on the controllable fabrication of MnO 2 nanobuilding blocks, tumor targeting accumulation, working mechanisms of enhancing therapeutic efficacy, and the necessary considerations for construction of all-in-one nanoplatform. Finally, the current challenges and future directions in this rapidly growing research field are also discussed, which will provide guidance on the future works about the clinical translation of MnO 2-based all-in-one nanoplatform. 1. Introduction Cancer is one of the life-threatening diseases with high annual mortality rate. Due to the abnormal structure of tumor blood vessels, abnormal proliferation, and special metabolic patterns of tumor cells, the tumor microenvironment (TME) displays obvious abnormal characteristics, such as hypoxia, high H 2 O 2 and glutathione (GSH) concentration, and low pH (4.5-5.0). [1] Despite many efforts have been made to develop new strategies for cancer therapy, heterogeneous tumoral tissue and unique TME limited the therapeutic efficacy. [2] The results obtained from laboratory research and preclinical practice indicate that monotherapy cannot completely eradicate the tumor

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The impact of manganese on neurotransmitter systems

Cited by 39 publications

References 122 publications

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts

Construction of Smart Manganese Dioxide‐Based All‐in‐One Nanoplatform for Cancer Diagnosis and Therapy

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