Document Detail


Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis.
MedLine Citation:
PMID:  21399558     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Peter J Giannone; Alicia A Alcamo; Brandon L Schanbacher; Craig A Nankervis; Gail E Besner; John A Bauer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Pediatric research     Volume:  70     ISSN:  1530-0447     ISO Abbreviation:  Pediatr. Res.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-09     Completed Date:  2011-10-07     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0100714     Medline TA:  Pediatr Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  67-71     Citation Subset:  IM    
Affiliation:
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA. peter.giannone@nationwidechildrens.org
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Animals, Newborn
Cell Death / drug effects
Disease Models, Animal
Enterocolitis, Necrotizing / drug therapy*,  enzymology,  pathology
Enzyme Activation
Enzyme Inhibitors / pharmacology*
Humans
Infant, Newborn
Intestinal Mucosa / drug effects*,  enzymology,  pathology
Intestines / drug effects*,  enzymology,  pathology
Niacinamide / pharmacology*
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / antagonists & inhibitors,  metabolism
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*,  metabolism
Rats
Rats, Sprague-Dawley
Tyrosine / analogs & derivatives,  metabolism
Grant Support
ID/Acronym/Agency:
1K23DK078909/DK/NIDDK NIH HHS; K23 DK078909/DK/NIDDK NIH HHS; K23 DK078909-01A1/DK/NIDDK NIH HHS; K23 DK078909-01A1S1/DK/NIDDK NIH HHS; K23 DK078909-02/DK/NIDDK NIH HHS; K23 DK078909-03/DK/NIDDK NIH HHS; K23 DK078909-05/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 10102-43-9/Nitric Oxide; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; 98-92-0/Niacinamide; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, rat; EC 2.4.2.30/Adprt protein, rat; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases
Comments/Corrections

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