Role of glial cells in manganese neurotoxicity

Filipov, Nikolay M.; Dodd, Celia A.

doi:10.1002/jat.1762

Cited by 57 publications

(50 citation statements)

References 102 publications

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“…26,27) Mn can induce neuronal damage directly and also indirectly enhance neuronal cell death through activation of microglia. 28) Microglia easily respond to Mn and release ROS and inflammatory mediators, such as proinflammatory cytokines, nitric oxide (NO), and prostaglandins, inducing detrimental toxicity to neighboring neurons. 27) Although there are limited reports on the effects of Mninduced toxicity on glial cells, some studies suggested that self-produced ROS can stimulate degradation of ferritin in microglia and subsequent microglial cell death.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Curcumin on Manganese-Induced BV-2 Microglial Cell Death

Park

Chun

2017

Biological & Pharmaceutical Bulletin

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Curcumin, a bioactive component in tumeric, has been shown to exert antioxidant, anti-inflammatory, anticarcinogenic, hepatoprotective, and neuroprotective effects, but the effects of curcumin against manganese (Mn)-mediated neurotoxicity have not been studied. This study examined the protective effects of curcumin on Mn-induced cytotoxicity in BV-2 microglial cells. Curcumin (0.1-10 µM) dose-dependently prevented Mn (250 µM)-induced cell death. Mn-induced mitochondria-related apoptotic characteristics, such as caspase-3 and -9 activation, cytochrome c release, Bax increase, and Bcl-2 decrease, were significantly suppressed by curcumin. In addition, curcumin significantly increased intracellular glutathione (GSH) and moderately potentiated superoxide dismutase (SOD), both which were diminished by Mn treatment. Curcumin pretreatment effectively suppressed Mn-induced upregulation of malondialdehyde (MDA), total reactive oxygen species (ROS). Moreover, curcumin markedly inhibited the Mn-induced mitochondrial membrane potential (MMP) loss. Furthermore, curcumin was able to induce heme oxygenase (HO)-1 expression. Curcuminmediated inhibition of ROS, down-regulation of caspases, restoration of MMP, and recovery of cell viability were partially reversed by HO-1 inhibitor (SnPP). These results suggest the first evidence that curcumin can prevent Mn-induced microglial cell death through the induction of HO-1 and regulation of oxidative stress, mitochondrial dysfunction, and apoptotic events.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Curcumin on Manganese-Induced BV-2 Microglial Cell Death

Park

Chun

2017

Biological & Pharmaceutical Bulletin

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“…65 Moreover, Mn potentiates the release of several inflammatory molecules such as prostaglandins, cytokines including TNF-a, Interleukin (IL)-6, and IL-1b, and nitric oxide from the activated glial cells. [66][67][68][69] Among these inflammatory cytokines, TNF-a and IL-1b have been shown to decrease GLT-1 mRNA and protein expression levels in astrocytes, acting as negative regulators of GLT-1. 70,71 Mn induces nitric oxide synthase 2 (NOS2, an inflammatory gene) via NFkB activation in astrocytes.…”

Section: Apoptosis and Inflammationmentioning

confidence: 99%

Mechanism of Manganese-Induced Impairment of Astrocytic Glutamate Transporters

Karki¹,

Smith²,

Aschner³

et al. 2014

Manganese in Health and Disease

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Manganese (Mn) is an essential trace element, playing a vital role in numerous biochemical and cellular reactions; however, chronic exposure to high Mn levels from environmental and occupational sources causes a neurological disorder with shared features of Parkinson's disease (PD), referred to as manganism. Despite well-established pathological signs, the molecular mechanism(s) by which Mn induces these neurological disorders still remain to be established. In addition to oxidative stress and impairment of mitochondria, Mn dysregulates astrocytic glutamate transporters (GLAST [glutamate aspartate transporter] and GLT-1 [glutamate transporter 1]) by decreasing their promoter activity, mRNA, and protein levels as well as astrocytic glutamate uptake. The Mn-induced impairment in glutamate transporters is directly associated with excitotoxic neuronal death because the astrocytic glutamate transporters, GLAST and GLT-1, are mainly responsible for maintaining optimal glutamate levels in the synaptic clefts, thereby preventing glutamate-induced neuronal excitotoxicity. It is widely recognized that reduced expression and function of astrocytic glutamate transporters, in particular GLT-1, are associated with various neurodegenerative diseases, including PD and amyotrophic lateral sclerosis (ALS). Therefore, Mn-induced impairment of astrocytic glutamate transporters might be a critical mechanism for Mn neurotoxicity. Our latest studies have uncovered a novel mechanism of Mn-induced repression of GLT-1 at the transcriptional level. It appears that the transcription factor yin yang 1 (YY1) plays a critical role in Mn-induced repression of GLT-1 promoter activity and expression. Herein, we will discuss the cellular and molecular mechanisms by which Mn induces neurotoxicity, such as oxidative stress, mitochondrial impairment, inflammation, and dysregulation of glutamate transporters.

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“…High doses of Mn have been shown to induce production of the cytokines TNF-alpha, IL1-beta, and IL-6 and the production of hydrogen peroxide 98,99 . Mn also increased the production of both cytokines and free radicals when cells were simultaneously stimulated with LPS.…”

Section: Microglial Activation and Inflammationmentioning

confidence: 99%

“…Mn also increased the production of both cytokines and free radicals when cells were simultaneously stimulated with LPS. The production of cytokines proceeds through the activation of the neuroinflammatory NFkappa-B and the MAP kinase p38 [98][99][100] . The release of both cytokines and free radical reactive oxygen and nitrogen species from Mn activated microglia can exert deleterious effects on neighboring neurons.…”

Section: Microglial Activation and Inflammationmentioning

confidence: 99%