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  Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures

de Bernardo, S., Canals, S., Casarejos MJ, Solana RM, Menendez, J., & Mena, M. (2004). Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. Journal of Neurochemistry, 91(3), 667-682. doi:10.1111/j.1471-4159.2004.02744.x.

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de Bernardo, S, Author
Canals, S1, Author           
Casarejos MJ, Solana RM, Menendez, J, Author
Mena, MA, Author
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1Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497794              

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 Abstract: To date, glutathione (GSH) depletion is the earliest biochemical alteration shown in brains of Parkinson‘s disease patients, but the role of GSH in dopamine cell survival is debated. In this study we show that GSH depletion, produced with GSH synthesis inhibitor, l-buthionine-(S,R)-sulfoximine (BSO), induces selectively neuronal cell death in neuron/glia, but not in neuronal-enriched midbrain cultures and that cell death occurs with characteristics of necrosis and apoptosis. BSO produces a dose- and time-dependent generation of reactive oxygen species (ROS) in neurons. BSO activates extracellular signal-regulated kinases (ERK-1/2), 4 and 6 h after treatment. MEK-1/2 and lipoxygenase (LOX) inhibitors, as well as ascorbic acid, prevent ERK-1/2 activation and neuronal loss, but the inhibition of nitric oxide sintase (NOS), cyclo-oxygenase (COX), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) does not have protective effects. Co-localization studies show that p-ERK-1/2 expression after BSO treatment increased in astrocytes and microglial cells, but not in neurons. Selective metabolic impairment of glial cells with fluoroacetate decreased ERK activation. However, blockade of microglial activation with minocycline did not. Our results indicate that neuronal death induced by GSH depletion is due to ROS-dependent activation of the ERK-1/2 signalling pathway in glial cells. These data may be of relevance in Parkinson‘s disease, where GSH depletion and glial dysfunction have been documented.

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 Dates: 2004-11
 Publication Status: Issued
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Title: Journal of Neurochemistry
Source Genre: Journal
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Pages: - Volume / Issue: 91 (3) Sequence Number: - Start / End Page: 667 - 682 Identifier: -