Manganese Augments Nitric Oxide Synthesis in Murine Astrocytes: A New Pathogenetic Mechanism in Manganism?

Spranger, Matthias; Schwab, Stefan; Desiderato, Stephanie; Bonmann, Eckhard; Krieger, Derk; Fandrey, Joachim

doi:10.1006/exnr.1997.6666

Cited by 77 publications

(69 citation statements)

References 29 publications

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“…These data are consistent with our earlier observations (42) that used manganese chloride (100 M) as well as with those of other investigators (11,43). Although it is generally believed that induction of the MPT leads to cell death (apoptosis and or necrosis), several reports indicate that the MPT is a reversible process (16,44).…”

Section: Figsupporting

confidence: 93%

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Rao¹,

Norenberg

2004

Journal of Biological Chemistry

116

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Manganese is known to cause central nervous system injury leading to parkinsonism and to contribute to the pathogenesis of hepatic encephalopathy. Although mechanisms of manganese neurotoxicity are not completely understood, chronic exposure of various cell types to manganese has shown oxidative stress and mitochondrial energy failure, factors that are often implicated in the induction of the mitochondrial permeability transition (MPT). In this study, we examined whether exposure of cultured neurons and astrocytes to manganese induces the MPT. Cells were treated with manganese acetate (10 -100 M), and the MPT was assessed by changes in the mitochondrial membrane potential and in mitochondrial calcein fluorescence. In astrocytes, manganese caused a dissipation of the mitochondrial membrane potential and decreased the mitochondrial calcein fluorescence in a concentration-and time-dependent manner. These changes were completely blocked by pretreatment with cyclosporin A, consistent with induction of the MPT. On the other hand, similarly treated cultured cortical neurons had a delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in astrocytes was blocked by pretreatment with antioxidants, suggesting the potential involvement of oxidative stress in this process. Induction of the MPT by manganese and associated mitochondrial dysfunction in astrocytes may represent key mechanisms in manganese neurotoxicity.Manganese is an essential element and an integral component of key enzymes such as glutamine synthetase and mitochondrial superoxide dismutase (Mn-SOD) 1 (1). However, excess deposition of manganese in the central nervous system often leads to neurological abnormalities, including manganism, the symptoms of which (hypokinesis, rigidity, and tremor) resemble Parkinson's disease (2). Manganism is an occupational health problem in workers employed in welding factories, manganese mines, and ferro-alloy plants (3). In addition, the widespread use of the manganese derivative methylcyclopentadienyl manganese as an anti-knock agent in gasoline has evolved into a major environmental issue (4). Further, manganese toxicity has been implicated in the mechanism of hepatic encephalopathy, a neurological condition associated with chronic liver failure (5, 6).The mechanisms of manganese neurotoxicity are not completely understood. Several reports propose that manganese neurotoxicity is mainly associated with mitochondrial dysfunction (7), leading to decreased oxidative phosphorylation (8). Manganese has also been shown to induce oxidative stress (9 -11).Oxidative stress is considered a major factor in the induction of the mitochondrial permeability transition (MPT) (12, 13). The MPT is a Ca ϩ2 -dependent process often associated with various other factors (14). The MPT is characterized by opening of the permeability transition pore in the inner mitochondrial membrane, resulting in increased permeability of this membrane to protons, ions, and other solutes Յ1500 Da. This increased permeability leads to a coll...

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Section: Figsupporting

confidence: 93%

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Rao¹,

Norenberg

2004

Journal of Biological Chemistry

116

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“…This assertion is supported by more recent studies that noted an early upregulation of the 'peripheral-type' (mitochondrial) benzodiazepine receptor in adult rats exposed subacutely to Mn that was associated with Alzheimer type-II astrocytosis in the globus pallidus . Spranger et al (1998) speculated that activated astrocytes contribute to Mn neurotoxicity through excessive production of NO based upon their data demonstrating that Mn-induced neuronal injury required the presence of astrocytes and was associated with increased expression of the inducible isoform of nitric oxide synthase (NOS2). Collectively, these studies suggested that debilitation of astrocytic mitochondrial function and increased production of NO could be salient mechanisms in Mn neurotoxicity.…”

Section: Inflammatory Activation Of Gliamentioning

confidence: 99%

“…Mn enhances the release of inflammatory cytokines interleukin-6 and TNF-α from microglial cells (Chang and Liu 1999;Filipov et al 2005) that can promote the activation of astrocytes and subsequent release of inflammatory mediators such as prostaglandin E2 and nitric oxide (NO) Hirsch et al 1998;Spranger et al 1998). Mn also strongly potentiates NO production in cytokine-stimulated astrocytes, leading to apoptosis in co-cultured neurons Spranger et al 1998;Tjalkens et al 2008).…”

Section: Inflammatory Activation Of Gliamentioning

confidence: 99%

“…Mn also strongly potentiates NO production in cytokine-stimulated astrocytes, leading to apoptosis in co-cultured neurons Spranger et al 1998;Tjalkens et al 2008). This observation is supported by studies demonstrating increased expression of NOS2 in activated astrocytes surrounding degenerating neurons in the striatum and globus pallidus of Mn-treated mice .…”

Section: Inflammatory Activation Of Gliamentioning

confidence: 99%

“…Mn also enhances the capacity of bacterial lipopolysaccharide to promote NO production in both astroglial (Barhoumi et al 2004) and microglial (Filipov et al 2005) cells. Low concentrations of Mn can increase the capacity of TNF-α, interferon-γ, and IL-1β to induce expression of NOS2 and production of NO in astrocytes by promoting activation of the transcription factor NF-κB (Liu et al 2005;Spranger et al 1998). The mechanism underlying the pronounced effect of lowlevel Mn on expression of NOS2 in astrocytes appears to reside in the capacity of the divalent metal to potently stimulate soluble guanylate cyclase, leading to elevated intracellular levels of cGMP and MAP kinase-dependent activation of NF-κB ).…”

Section: Inflammatory Activation Of Gliamentioning

confidence: 99%

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Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

et al. 2009

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Abstract:The purpose of this review is to highlight recent advances in the neuropathology associated with Mn exposures. We commence with a discussion on occupational manganism and clinical aspects of the disorder. This is followed by novel considerations on Mn transport (see also chapter by Yokel, this volume), advancing new hypotheses on the involvement of several transporters in Mn entry into the brain. This is followed by a brief description of the effects of Mn on neurotransmitter systems that are putative modulators of dopamine (DA) biology (the primary target of Mn neurotoxicity), as well as its effects on mitochondrial dysfunction and disruption of cellular energy metabolism. Next, we discuss inflammatory activation of glia in neuronal injury and how disruption of synaptic transmission and glial-neuronal communication may serve as underlying mechanisms of Mn-induced neurodegeneration commensurate with the cross-talk between glia and neurons. We conclude with a discussion on therapeutic aspects of Mn exposure. Emphasis is directed at treatment modalities and the utility of chelators in attenuating the neurodegenerative sequelae of exposure to Mn. For additional reading on several topics inherent to this review as well as others, the reader may wish to consult Aschner and Dorman (Toxicological Review 25:147-154, 2007) and Bowman et al. (Metals and neurodegeneration, 2009).

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Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration

Fujioka

Taoka

Matsuo

et al. 2003

Annals of Neurology

122

138

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Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.

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Manganese Augments Nitric Oxide Synthesis in Murine Astrocytes: A New Pathogenetic Mechanism in Manganism?

Cited by 77 publications

References 29 publications

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Manganese and its Role in Parkinson’s Disease: From Transport to Neuropathology

Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration

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