Estrogen Alleviates Oxidative Bowel Injury and Neuroinflammation in Necrotizing Enterocolitis.

Abstract

Introduction: High mortality and morbidity of neonates with necrotizing enterocolitis (NEC) necessitates the investigation of novel therapies to improve outcomes. It was aimed to elucidate the potential therapeutic effect of estrogen receptor agonists on NEC-induced intestinal and brain injury in rats.

Methods: Sprague-Dawley pups of both sexes were separated from their mothers at postnatal 5^th d. Feeding with formula along with a single session of hypoxia was applied to induce NEC, while control pups were kept with their mothers. The NEC rats received either vehicle, estrogen receptor α (ERα) agonist propyl pyrazole triol (1 mg/kg/day), ERβ agonist diarylpropionitrile (1 mg/kg/day), or 17β-estradiol (1 mg/kg/day) during maternal separation. All pups were decapitated on postnatal 9^th d to collect intestinal and brain tissue samples.

Results: Elevation in proinflammatory cytokines, apoptosis, and microscopically and biochemically evident oxidative injury in both the intestinal and brain tissues were observed in NEC-induced pups. In both the intestinal and brain tissues, nerve growth factor and brain-derived neurotrophic factor protein levels were depleted, expressions of both the ESR1 and ESR2 genes were downregulated, while treatment with 17β-estradiol or ER agonists alleviated extent of oxidative injury of the intestines and brain tissue, upregulated nerve growth factor, brain-derived neurotrophic factor, and ER gene expressions, abolished NEC-induced decrease in claudin-3 expression, increased the survival rates, improved the clinical states of the survived pups at varying degrees.

Conclusions: Activation of estrogen signaling by receptor agonists alleviated NEC-induced intestinal and cerebral injury, implicating that estrogen agonists could be regarded as promising preventive/therapeutic agents for NEC.