β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations

Abstract

Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The β3-adrenoreceptor (β3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the β3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague–Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing β3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for β3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.

Inside the Biology of the β3-Adrenoceptor

“…Early human placental tissue matured under a hypoxic environment necessary to induce specific placental metabolic activities [153]. The premature contact of immature organs with oxygenated ambientes, which have a moderate hyperoxic environment compared to physiologic intra-uterine hypoxia, could control their growing process by reducing β3-AR expression and impairing its role in organ maturation [154].…”

β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation

“…In this study, we report how exposure to high concentrations of oxygen induces severe anatomical damage to the colon and a significant reduction in the number of colonic cells expressing β3-AR. Interestingly, the administration of a β3-AR agonist significantly prevented colonic length reduction, restored the production of mucins, and, surprisingly, reduced the alteration of the colonic myenteric plexus [ 60 ], suggesting that β3-AR agonism may represent a future therapeutic option for disorders induced by hyperoxia-impaired development, typical of prematurity disorders.…”