Diethylmaleate and iodoacetate in combination caused profound cell death in astrocytes. (20th May 2013)

• Record Type: Journal Article
• Authors: Liao, Su‐Lan; Ou, Yen‐Chuan; Chang, Cheng‐Yi; Chen, Wen‐Ying; Kuan, Yu‐Hsiang; Wang, Wen‐Yi; Pan, Hung‐Chuan; Chen, Chun‐Jung
• Is Part Of: Journal of neurochemistry. Volume 127:Number 2(2013:Oct.)
• Page Start: 271
• Page End: 282
• Publication Date: 2013-05-20
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12291
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12291-abs-0001"> <title>Abstract</title> <p>Energy failure and oxidative stress have been implicated in the pathogenesis of ischemia. Here, we report a potential link between cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>) 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 cPLA<sub>2</sub> 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 <italic>N</italic>, <italic>N</italic>, <italic>N</italic>′, <italic>N</italic>′‐tetrakis(2‐pyridylmethyl)ethylenediamine. These observations indicate that ROS/PKC‐α, Src/Raf/ERK signaling and cPLA<sub>2</sub> 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.</p> <p> <boxed-text content-type="graphic" id="jnc12291-blkfxd-0001" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg3j5r4p52" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> </p> <p>Energy failure and oxidative stress have been implicated in the pathogenesis of ischemia and cell death. Through the application of the glycolytic inhibitor iodoacetate and the glutathione chelator diethylmaleate, we report a potential link between cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>) activation and energy failure/oxidative stress‐induced astrocyte damage involving reactive oxygen species (ROS), signaling through the kinases PKC‐α, Src, Raf, and ERK and concurrent elevation of endogenous chelatable zinc.</p> </abstract>