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Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model.

  • Zmora, Osnat1
  • Gutzeit, Ola2
  • Segal, Linoy2
  • Boulos, Sari2
  • Millo, Zvika2
  • Ginsberg, Yuval2
  • Khatib, Nizar2
  • Fainaru, Ofer2
  • Ross, Michael G3
  • Weiner, Zeev1
  • Beloosesky, Ron2
  • 1 Department of Pediatric Surgery, Shamir Medical Center, Zerifin, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. , (Israel)
  • 2 Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Ruth, and Bruce Rappaport Faculty of Medicine, Technion- Israel Institute of Technology, Haifa, Israel. , (Israel)
  • 3 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center and Los Angeles Biomedical Institute, Torrance, CA, USA.
Published Article
Acta Obstetricia Et Gynecologica Scandinavica
Wiley (Blackwell Publishing)
Publication Date
May 01, 2021
DOI: 10.1111/aogs.14054
PMID: 33247942


Preterm infants with necrotizing enterocolitis (NEC) are at increased risk of cerebral injury and neurodevelopmental dysfunction. N-acetyl-cysteine (NAC) is a known anti-inflammatory and antioxidant agent. Currently, there is no prophylactic treatment in clinical use to prevent NEC and its neurodevelopmental sequelae. We sought to determine whether brain inflammation/apoptosis accompanies NEC systemic inflammation, and whether it can be attenuated by maternal NAC treatment during pregnancy and/or in the neonatal period in a rat model. An established NEC newborn model (hypoxia 5% O2 for 10 min and formula feeding thrice daily, beginning on day 1 for 4 days) was used in Sprague-Dawley rat pups (n = 32). An additional group of pups (n = 33) received NAC (300 mg/kg intraperitoneal thrice daily) in addition to NEC conditions (NEC-NAC). Control pups (n = 33) were nursed and remained with the dam in room air. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg intravenous) in the last 3 days of pregnancy. After birth, pups were randomized into NAC-NEC (n = 33) with NEC conditions and NAC-NEC-NAC (n = 36) with additional postnatal NAC treatment. Pups were sacrificed on the fifth day of life. Pup serum interleukin (IL)-6 protein levels, and brain nuclear factor kappa B (NF-κB) p65, neuronal nitric oxide synthase (nNOS), Caspase 3, tumor necrosis factor alpha (TNF-α), IL-6 and IL-1β protein levels were determined by ELISA, western blot and TUNEL staining, and the groups were compared using analysis of variance (ANOVA). NEC pups had significantly increased serum IL-6 levels compared with the control group as well as increased neuronal apoptosis and brain protein levels of NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1β compared with control. In all NAC treatment groups, levels of serum IL-6, neuronal apoptosis and brain NF-κB, nNOS, Caspase 3, TNF-α, IL-6 and IL-1β protein levels were significantly reduced compared with the NEC group. The most pronounced decrease was demonstrated within the NAC-NEC-NAC group. NAC treatment can attenuate newborn inflammatory response syndrome and decrease offspring brain neuroapoptosis and inflammation in a rat model of NEC by inhibition of NF-κB, nNOS and Caspase 3 pathways. © 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.

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