title: Glucose exacerbates zinc-induced astrocyte death.
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-α (PKC-α)/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-α membrane translocation, 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-α/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-α/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.
authors.affiliation: Department of Surgery, Fong Yuan Hospital, Taichung, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.forename: Tsung-Kuei
authors.initials: TK
authors.lastname: Kao
authors.forename: Hung-Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Wang
authors.forename: Hsi-Chi
authors.initials: HC
authors.lastname: Lu
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017967:Zinc Compounds / Q000633:toxicity*
chemical_list: D002712:Chlorides; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C016837:zinc chloride; D007770:L-Lactate Dehydrogenase; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D054467:Phospholipases A2; D005947:Glucose