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J Neurochem. 2013 Oct;127(2):271-82. doi: 10.1111/jnc.12291. Epub 2013 May 20.

Diethylmaleate and iodoacetate in combination caused profound cell death in astrocytes.

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  • 1Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.

Abstract

Energy failure and oxidative stress have been implicated in the pathogenesis of ischemia. Here, we report a potential link between cytosolic phospholipase A₂ (cPLA₂) activation and energy failure/oxidative stress-induced astrocyte damage involving reactive oxygen species (ROS), protein kinase C-α (PKC-α), Src, Raf, and extracellular signal-regulated kinase (ERK) signaling and concurrent elevation of endogenous chelatable zinc. Energy failure and oxidative stress were produced by treating astrocytes with glycolytic inhibitor iodoacetate and glutathione chelator diethylmaleate, respectively. Diethylmaleate and iodoacetate in combination caused augmented damage to astrocytes in a time- and concentration-dependent manner. The cell death caused by diethylmaleate/iodoacetate was accompanied by increased ROS generation, PKC-α membrane translocation, Src, Raf, ERK, and cPLA₂ phosphorylation. Pharmacological studies revealed that these activations all contributed to diethylmaleate/iodoacetate-induced astrocyte death. Intriguingly, the mobilization of endogenous chelatable zinc was observed in diethylmaleate/iodoacetate-treated astrocytes. Zinc appears to act as a downstream mediator in response to diethylmaleate/iodoacetate treatment because of the attenuating effects of its chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine. These observations indicate that ROS/PKC-α, Src/Raf/ERK signaling and cPLA₂ are active participants in diethylmaleate/iodoacetate-induced astrocyte death and contribute to a vicious cycle between the depletion of ATP/glutathione and the mobilization of chelatable zinc as critical upstream effectors in initiating cytotoxic cascades.

© 2013 International Society for Neurochemistry.

KEYWORDS:

astrocyte; energy failure; oxidative stress; zinc

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