Paraquat-induced apoptotic cell death in cerebellar granule cells

González‐Polo, Rosa A.; Rodrı́guez-Martı́n, Andrea; Morán, José M.; Niso, Mireia; Soler, Germán; Fuentes, José

doi:10.1016/j.brainres.2004.02.078

Cited by 92 publications

(60 citation statements)

References 30 publications

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“…Sakai et al (1995) found that superoxide levels and cytotoxicity in bovine endothelial cells exposed to PQ were reduced in cells treated with allopurinol. In cerebellar granule cells treated with PQ, allopurinol partially prevented the release of cytochrome C from mitochondria and thus, inhibited PQ-induced apoptosis (Gonzalez-Polo et al, 2004).…”

Section: Discussionmentioning

confidence: 94%

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Domico

Cooper

Bernard³

et al. 2007

NeuroToxicology

122

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Previous in vitro studies in our laboratory have shown that mancozeb (MZ) and maneb (MB), both widely used EBDC fungicides, are equipotent neurotoxicants that produce cell loss in mesencephalic dopaminergic and GABAergic cells after an acute 24 h exposure. Mitochondrial uncoupling and inhibition were associated with fungicide exposure. Inhibition of mitochondrial respiration is known to increase free radical production. Here the mechanism(s) of neuronal damage associated with MZ exposure was further explored by determining the role that reactive oxygen species (ROS) played in toxicity. Damage to mesencephalic dopamine and GABA cell populations were significantly attenuated when carried out in the presence of ascorbate or SOD indicative of a free radical mediated contribution to toxicity. ROS generation monitored by H 2 O 2 production using Amplex Red increased in a dose-dependent manner in response to MZ. Inhibition of intracellular catalase with aminotriazole had little effect on H 2 O 2 generation, whereas exogenously added catalase significantly reduced H 2 O 2 production demonstrating a large extracellular contribution to ROS generation. Conversely, cells preloaded with the ROS indicator dye DCF showed significant MZ-induced ROS production, demonstrating an increase in intracellular ROS. Both the organic backbone of MZ as well as its associated Mn ion, but not Zn ion were responsible and required for H 2 O 2 generation. The functionally diverse NADPH oxidase inhibitors, diphenylene iodonium chloride, apocynin, and 4-(2-aminoethyl)benzene-sulfonyl fluoride hydrochloride significantly attenuated H 2 O 2 production by MZ. In growth medium lacking cells, MZ produced little H 2 O 2 , but enhanced H 2 O 2 generation when added with xanthine plus xanthine oxidase whereas, in cultured cells, allopurinol partially attenuated H 2 O 2 production by MZ. Minocycline, an inhibitor of microglial activation, modestly reduced H 2 O 2 formation in mesencephalic cells. In contrast, neuronal enriched cultures or cultures treated with MAC-1-SAP to kill microglia, did not show an attenuation of ROS production. These findings demonstrate that Mn-containing EBDC fungicides such as MZ and MB can produce robust ROS generation that likely occurs via redox cycling with extracellular and intracellular oxidases. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2008 November 1. The findings further show that microglia may contribute to but are not required for ROS production by MZ.

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Section: Discussionmentioning

confidence: 94%

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Domico

Cooper

Bernard³

et al. 2007

NeuroToxicology

122

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“…Increases in ROS production by oxidases in the mitochondrial respiratory chain have been regarded as an important process for toxin-induced apoptosis (Gonzalez-Polo et al, 2004;McCarthy et al, 2004). Mitochondrial dysfunction and mitochondrial-induced apoptosis have been demonstrated in paraquat toxicity in dopaminergic cells (Gomez et al, 2007;GonzalezPolo et al, 2004;McCarthy et al, 2004;Richardson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCδ) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCδ inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCδ-and ERK-dependent pathways.

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“…On the other hand, oxidantinduced damage to DNA is known to activate the intrinsic pathway, resulting in permeabilization of the outer mitochondrial membrane and release of molecules normally confined to the mitochondrial intermembrane space, such as cytochrome c; procaspases-2, -3, and -9; and apoptosis-inducing factor (3,8,12). Furthermore, XOD reportedly plays a key role in the ROS production that precedes the apoptotic cascade and cell death associated with reductions in mitochondrial cytochrome c content and caspase-3 activity (11,32), and production of ROS followed by the release of cytochrome c and activation of caspase-9 reportedly causes mitochondria-regulated cell death in alveolar epithelial cells (27). We therefore suggest that it is most likely the intrinsic pathway that mediates apoptosis in our model.…”

Section: Discussionmentioning

confidence: 66%

Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung

Saitô¹,

Ogawa²,

Minamiya³

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Saito, Satoshi, Jun-ichi Ogawa, and Yoshihiro Minamiya. Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung. Am J Physiol Lung Cell Mol Physiol 289: L400 -L406, 2005. First published May 6, 2005; doi:10.1152/ajplung.00136.2005.-The pathogenesis of reexpansion pulmonary edema is not yet fully understood. We therefore studied its mechanism in a rat model in which the left lung was collapsed by bronchial occlusion for 1 h and then reexpanded and ventilated for an additional 3 h. We then evaluated the production of reactive oxygen species in the lungs using fluorescent imaging and cerium deposition electron microscopic techniques and the incidence of apoptosis using the TdT-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. We found that pulmonary reexpansion induced production of reactive oxygen species and then apoptosis, mainly in endothelial and alveolar type II epithelial cells. Endothelial cells and alveolar type I and II epithelial cells in the reexpanded lung were positive for TUNEL and cleaved caspase-3. DNA fragmentation was also observed in the reexpanded lung. In addition, wet-dry ratios obtained with reexpanded lungs were significantly higher than those obtained with control lungs, indicating increased fluid content. All of these effects were attenuated by pretreating rats with a specific xanthine oxidase inhibitor, sodium (Ϫ)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one. It thus appears that pulmonary reexpansion activates xanthine oxidase in both endothelial and alveolar type II epithelial cells and that the reactive oxygen species produced by the enzyme induce apoptosis among the endothelial and alveolar type I and II epithelial cells that make up the pulmonary water-air barrier, leading to reexpansion pulmonary edema.reactive oxygen species; caspase-3; type II alveolar epithelial cell; reoxygenation REEXPANSION PULMONARY EDEMA (RPE) is a rare complication of the treatment of lung collapse secondary to pneumothorax, pleural effusion, or atelectasis. Although physicians generally believe that, unlike acute respiratory distress syndrome (ARDS), RPE does not require intensive care, the outcome of RPE is reportedly fatal in 20% of patients (17). Moreover, reexpansion after atelectatic storage for hypothermic preservation of lungs before transplantation may be responsible for postpreservation and postreperfusion lung injury (7).The mechanism responsible for RPE is not fully understood. It has been suggested that after atelectasis the mechanical stresses related to lung inflation may cause RPE (28). This effect has also been mentioned as a contributor to the pathogenesis of postpreservation lung injury (9). In addition, some evidence suggests changes in alveolar surfactant may contribute to RPE (26,31), and a number of investigators have reported that neutrophil accumulation in the lung induced by various chemokines (e.g., IL-8 and monocyte chemoattractant protein-1), chemical mediators, and adhesion molecules (24, 30) plays a major role in ...

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Paraquat-induced apoptotic cell death in cerebellar granule cells

Cited by 92 publications

References 30 publications

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Pulmonary reexpansion causes xanthine oxidase-induced apoptosis in rat lung

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