Central role of PKCdelta 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) delta activity was increased approximately 2-fold, and DNA binding activity of redox-sensitive transcription factor activator protein-1 (AP-1) was enhanced 2.5-fold. A relationship among oxidative stress, PKCdelta activity, AP-1 activation, and apoptosis was demonstrated by pretreating neurons with 500 muM vitamin E, with 20 mug/ml Ginkgo biloba extract, or with 3 muM Rottlerin, inhibitor of PKCdelta; these pretreatments were able to protect neurons from the glycoxidation-dependent effects.
Nitti
Mariapaola
M
Department of Experimental Medicine, Section of General Pathology, University of Genoa, 16132 Genoa, Italy.
d'Abramo
Cristina
C
Traverso
Nicola
N
Verzola
Daniela
D
Garibotto
Giacomo
G
Poggi
Alessia
A
Odetti
Patrizio
P
Cottalasso
Damiano
D
Marinari
Umberto M
UM
Pronzato
Maria A
MA
Domenicotti
Cinzia
C
D000098:Acetophenones / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051745:Protein Kinase C-delta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D000098:Acetophenones; D000975:Antioxidants; D001578:Benzopyrans; D017127:Glycation End Products, Advanced; D047428:Protein Kinase Inhibitors; D018808:Transcription Factor AP-1; D014810:Vitamin E; D001120:Arginine; C062187:pentosidine; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D008239:Lysine