Glucose exacerbates zinc-induced astrocyte death

Zinc and cytosolic phospholipase A2 (cPLA2) 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 cPLA2 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 ZnCl2 was accompanied by increased ROS generation, PKC-α membrane translocation, ERK phosphorylation, and cPLA2 phosphorylation and activity. Pharmacological studies revealed that these activations contributed to ZnCl2-induced astrocyte death. Mechanistic studies had suggested that ROS/PKC-α/ERK was a potential signal linking zinc and cPLA2. Glucose increased zinc uptake and potentiated ZnCl2-induced alterations and astrocyte death. These observations indicated that ROS/PKC-α/ERK signaling and cPLA2 were actively involved in zinc-induced astrocyte damage, and suggested zinc was a potential downstream effector in hyperglycemia-aggravated astrocyte injury.