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: Peter J Giannone, Alicia A Alcamo, Brandon L Schanbacher, Craig A Nankervis, Gail E Besner, John A Bauer
• Journal: Pediatric research (Pediatr Res) Vol. 70 Issue 1 Pg. 67-71 (Jul 2011) ISSN: 1530-0447 [Electronic] United States
• PMID: 21399558 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Niacinamide
• Nitric Oxide
• 3-nitrotyrosine
• Tyrosine
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• PARP1 protein, human
• Parp1 protein, rat
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• 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) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Tyrosine (analogs & derivatives, metabolism)