Toxicology Letters 199 (2010) 102–109 Contents lists available at ScienceDirect Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet Glucose exacerbates zinc-induced astrocyte death Cheng-Yi Chang a,b,1 , Yen-Chuan Ou c,1 , Tsung-Kuei Kao d , Hung-Chuan Pan b , Shih-Yi Lin e , Su-Lan Liao f , Wen-Yi Wang g , Hsi-Chi Lu h , Chun-Jung Chen f,i,∗ a Department of Surgery, Fong Yuan Hospital, Taichung, Taiwan b Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, Taiwan c Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan d Department of Nursing, Tajen University, Pingtung, Taiwan e Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan f Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan g Graduate School of Nursing, Hung-Kuang University, Taichung, Taiwan h Department of Food Science, Tunghai University, Taichung, Taiwan i Center for General Education, Tunghai University, Taichung, Taiwan article info Article history: Received 22 June 2010 Received in revised form 16 August 2010 Accepted 20 August 2010 Available online 26 August 2010 Keywords: Astrocyte Cytosolic phospholipase A2 Extracellular signal-regulated kinase Hyperglycemia Reactive oxygen species Zinc abstract Zinc and cytosolic phospholipase A 2 (cPLA 2 ) have been implicated in the death of neural cells and the pathogenesis of ischemia, and hyperglycemia is a potential augmenting factor. However, their potential crosstalk and/or interaction in mediating cell damage have not yet been fully elucidated. Here, we report that a potential link between cPLA 2 activation and zinc-induced astrocyte damage involving reactive oxygen species (ROS)/protein kinase C- (PKC-)/extracellular signal-regulated kinase (ERK) signaling and glucose is able to increase zinc uptake and potentiate zinc-induced alterations and astrocyte damage. The cell death caused by ZnCl 2 was accompanied by increased ROS generation, PKC- membrane translo- cation, ERK phosphorylation, and cPLA 2 phosphorylation and activity. Pharmacological studies revealed that these activations contributed to ZnCl 2 -induced astrocyte death. Mechanistic studies had suggested that ROS/PKC-/ERK was a potential signal linking zinc and cPLA 2 . Glucose increased zinc uptake and potentiated ZnCl 2 -induced alterations and astrocyte death. These observations indicated that ROS/PKC- /ERK signaling and cPLA 2 were actively involved in zinc-induced astrocyte damage, and suggested zinc was a potential downstream effector in hyperglycemia-aggravated astrocyte injury. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction In the mammalian central nerve system (CNS), the transition metal zinc is localized exclusively to the synaptic vesicles of gluta- matergic neurons and has a special role as a modulator of synaptic transmission. Chelatable zinc is released into the synaptic cleft with the neurotransmitter during neuronal execution (Assaf and Chung, 1984). Under normal circumstances, the robust release of zinc is transient and is efficiently cleared from the synaptic cleft to assure the performance of successive stimuli. However, elevated levels of extracellular zinc in pathological conditions are thought to con- tribute to the resulting neuropathology (Choi and Koh, 1998; Côté et al., 2005; Li et al., 2009). ∗ Corresponding author at: Department of Education and Research, Taichung Vet- erans General Hospital, No. 160, Sec. 3, Taichung-Kang Rd., Taichung 407, Taiwan. Tel.: +886 4 23592525x4022; fax: +886 4 23592705. E-mail addresses: cjchen@vghtc.gov.tw, cjchen9226@gmail.com (C.-J. Chen). 1 These authors contributed equally to this work. Zinc and ischemic cell death are linked because zinc translocates from presynaptic terminals into selectively vulnerable postsynap- tic neurons. Chelators such as CaEDTA block ischemia-induced zinc translocation and cell death (Kitamura et al., 2006). The accumu- lation of zinc in neurons and neuroprotection by zinc chelator occur in ischemia, trauma, and seizures (Choi and Koh, 1998; Suh et al., 2000; Kitamura et al., 2006; Stork and Li, 2009). This widening role for zinc toxicity underscores the importance of defining the mechanisms involved. Ischemia, head trauma, and intense seizures affect not only neurons but also impact glial cells (Choi and Koh, 1998; Lee et al., 2009; Stork and Li, 2009). The influx of cations, generation of oxidative stress, and failure of energy have been shown to be causes of zinc-mediated neu- ronal death (Kim et al., 1999; Sheline et al., 2000; Chen and Liao, 2003). There have been numerous investigations of zinc’s neuro- toxicity, but its role in glial cell death mechanisms has received relatively little attention. Zinc toxicity has been proposed as a likely alternative mechanism in massive glial death caused by mul- tiple injuries and disease states (Ryu et al., 2002; Bishop et al., 2007). 0378-4274/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2010.08.012