Inhibitors of poly(ADP-ribose) polymerase protect hippocampal neurons against genotoxic stress via PI-3K/AKT regulated pathway and by suppression of AIF translocation

• Autorzy: Cieslik M. , Jacewicz M. , Strosznajder J.B.
• Języki publikacji: EN

Abstrakty

EN

Poly(ADP-ribose)polymerase (PARP-1) plays a key role in DNA repair but its over activation has been proposed to be important in pathogenesis of brain ischemia and in neurodegenerative diseases. PARP catalyzes the conversion of bNAD+ to polymers of poly(ADP-ribose) (PAR) and is fully responsible for producing of PAR polymers during genotoxic stress. The last data indicated that PAR act at the mitochondria to induce cell death through stimulation of apoptosis inducing factor (AIF) release. However, the role of PAR in cell death seems to be complex and not fully elucidated. To better understand the role and relationship between AIF and PARP/PAR in death signaling the hippocampal neuronal (HT22) cells in culture were subjected to different concentration of DNA alkylating agent, 1-methyl-3-nitro-1-nitrosoguanidine (MNNG). The immunochemical and spectrophotometrical methods were applied. Consequently, HT22 cells treated with MNNG at 50ñ 500 mM demonstrated concentration dependent mitochondria failure and death. 24 h after 500 mM MNNG treatment only 15% of cells survive. PARP-1 inhibitors: 3-aminobenzamide (3AB) and PJ34 at 5 mM and 20 mM, respectively, protect most of the cells against MNNG induced death signaling. At lethal MNNG concentration PARP/PAR dependent AIF translocation from mitochondria is observed and the caspase independent death signaling is activated. Concomitantly PARP inhibitors affect the endogenous pathway regulated by PI-3K/AKT PKB/GSK-3 and infl uence the level of GSK-3β active form phosphorylated on Tyrosine 216. Summarizing our data indicated that inhibitors of PARP have positive effect on neuroprotective pathway regulated by PI-3K/AKT and on mitochondria function. Supported by Scientifi c Network of MS&HE No 28/E-32/SN0053/2007

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2009
• Tom: 69
• Numer: 1
• Opis fizyczny: p.95

Twórcy

autor

Cieslik M.

• Departament of Cellural Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Jacewicz M.

• Departament of Cellural Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder J.B.

• Departament of Cellural Signaling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland