Effect of poly (ADP-ribose) Polymerase-1 (PARP-1) inhibition on metabolic insults occuring at birth: promise and limitations

GRECIA.KASSANDRA, CHALKIDIKI, GREECE. MORALES P, SALECH F, KATUNAR M, CANOVAS J, KLAWITTER V, BUSTAMANETE D, KUKULJAN M, ANTONELLI M, COUVE A, HERRERA-MARSCHITZ

Grecia.Kassandra, Chalkidiki, Greece

Congreso; 10th International Congress on Amino Acid & Proteins; 2007

Interruption of oxygen availability and re-oxygenation at birth implies a severe metabolic insult, affecting the development of the central nervous system (CNS), increasing its vulnerability to challenges occurring at adult stages. It has been reported that perinatal asphyxia (PA) produces regionally specific neuronal decrease and neurite atrophy in basal ganglia, and hippocampus. In hippocampus, a concomitant increase of neurogenesis and neurite hypertrophy has also been observed. The potential neuroprotection of nicotinamide, a non-selective inhibitor of poly(ADP-ribose) polymerase (PARP-1), has been investigated), based on the idea that PA can trigger the overactivation of PARP-1, leading to NAD+ exhaustion and energy crisis, and to a caspase-independent apoptosis. In agreement, it has been found that nicotinamide, administered 1-24h after the insult (0.8 mmol/kg, i.p., 24, 48 and 72 h after birth.) can prevent some of the effects of PA, mainly in neostriatum, preventing a PA-induced decrease of the number of nNOS cells, and neurite atrophy. The effect of PA on neurite development has further been studied by lentivirus-mediated gene transfection of green fluorescence protein (GEP), monitored in vitro until the cultures are further treated for histochemistry.