Central role of PKCδ in glycoxidation-dependent apoptosis of human neurons

Accumulation of advanced glycation end products (AGEs) induces alterations in the intracellular redox balance, leading cells to functional injury. Current literature reports that intracellular signaling triggered by the interaction of AGEs with their specific receptors RAGEs depends on the cell type and the state of activation/stress. In this work, NT2 human neurons were exposed for 48 h to glycated fetal serum containing 750-3000 pmol/ml pentosidine; the treatment induced an increase in apoptosis rate linear with AGE concentration up to 1500 pmol/ml, but necrotic death was elicited with the highest AGE amount employed (3000 pmol/ml pentosidine). Pentosidine at 1500 pmol/ml, which was the concentration responsible for the highest apoptotic effect (40% of apoptotic neurons), was able to determine early generation of intracellular reactive oxygen species and increase in RAGE levels. Under these conditions, protein kinase C (PKC) 6 activity was increased approximately 2-fold, and DNA binding activity of redox-sensitive transcription factor activator protem-1 (AP-1) was enhanced 2.5-fold. A relationship among oxidative stress, PKC delta activity, AP-1 activation, and apoptosis was demonstrated by pretreating neurons with 500 mu M vitamin E, with 20 mu g/ml Ginkgo biloba extract, or with 3 mu M Rottlerin, inhibitor of PKC delta; these pretreatments were able to protect neurons from the glycoxidation-dependent effects. (c) 2004 Elsevier Inc. All rights reserved.