In:
Journal of Neurochemistry, Wiley, Vol. 127, No. 2 ( 2013-10), p. 271-282
Abstract:
Energy failure and oxidative stress have been implicated in the pathogenesis of ischemia. Here, we report a potential link between cytosolic phospholipase A 2 (cPLA 2 ) 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 2 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 cPLA 2 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. image 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 2 (cPLA 2 ) 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.
Type of Medium:
Online Resource
ISSN:
0022-3042
,
1471-4159
DOI:
10.1111/jnc.2013.127.issue-2
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2020528-4
SSG:
12
