title: Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis.
abstract: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC.
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA. peter.giannone@nationwidechildrens.org
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Giannone
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Alcamo
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Schanbacher
authors.forename: Craig A
authors.initials: CA
authors.lastname: Nankervis
authors.forename: Gail E
authors.initials: GE
authors.lastname: Besner
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009536:Niacinamide / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases