Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep

Abstract

Chronic hypobaric hypoxia during fetal and neonatal life induces neonatal pulmonary hypertension. Hypoxia and oxidative stress are driving this condition, which implies an increase generation of reactive oxygen species (ROS) and/or decreased antioxidant capacity. Melatonin has antioxidant properties that decrease oxidative stress and improves pulmonary vascular function when administered postnatally. However, the effects of an antenatal treatment with melatonin in the neonatal pulmonary function and oxidative status are unknown. Therefore, we hypothesized that an antenatal therapy with melatonin improves the pulmonary arterial pressure and antioxidant status in high altitude pulmonary hypertensive neonates. Twelve ewes were bred at high altitude (3600 m); 6 of them were used as a control group (vehicle 1.4% ethanol) and 6 as a melatonin treated group (10 mg d -1 melatonin in vehicle). Treatments were given once daily during the last third of gestation (100–150 days). Lambs were born and raised with their mothers until 12 days old, and neonatal pulmonary arterial pressure and resistance, plasma antioxidant capacity and the lung oxidative status were determined. Furthermore, we measured the pulmonary expression and activity for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the oxidative stress markers 8-isoprostanes, 4HNE and nitrotyrosine. Finally, we assessed pulmonary pro-oxidant sources by the expression and function of NADPH oxidase, mitochondria and xanthine oxidase. Melatonin decreased the birth weight. However, melatonin enhanced the plasma antioxidant capacity and decreased the pulmonary antioxidant activity, associated with a diminished oxidative stress during postnatal life. Interestingly, melatonin also decreased ROS generation at the main pro-oxidant sources. Our findings suggest that antenatal administration of melatonin programs an enhanced antioxidant/pro-oxidant status, modulating ROS sources in the postnatal lung.

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

“…Moreover, a recent study has shown that beyond the ability to induce antioxidant enzymatic expression and activity, melatonin can also modulate the production of pro-oxidant reactive oxygen species from their sources, such as the mitochondria, NADPH oxidase, and xanthine oxidase. 75 Therefore, melatonin may be achieving its antioxidant effects in our murine model of IUI through both increases in antioxidant enzymatic activities and decreases in pro-oxidant production. Further studies need to be done to discern the exact pathophysiology.…”

“…We showed that melatonin reduced oxidative stress markers, 4‐HNE, as well as pro‐inflammatory mediators and that melatonin activated the gene expression of SIRT1, Nrf2, and HO‐1 in the placenta. Moreover, a recent study has shown that beyond the ability to induce antioxidant enzymatic expression and activity, melatonin can also modulate the production of pro‐oxidant reactive oxygen species from their sources, such as the mitochondria, NADPH oxidase, and xanthine oxidase . Therefore, melatonin may be achieving its antioxidant effects in our murine model of IUI through both increases in antioxidant enzymatic activities and decreases in pro‐oxidant production.…”

El tratamiento postnatal con melatonina modula la expresión de agentes prostanoides en pulmón de neonatos de oveja con hipertensión pulmonar

“…Con respecto a lo anterior, se ha demostrado que melatonina disminuye el estrés oxidativo y la presión pulmonar en neonatos 15,16 y adultos 26 de modelos animales. Los efectos antioxidantes de melatonina están asociados a sus características de: 1) scavenger de radicales libres, 2) inducción de la maquinaria enzimática antioxidante y 3) disminución de la expresión de enzimas prooxidantes 27 , lo cual disminuye el tono oxidativo en el territorio pulmonar 15,17,18 . Además, melatonina puede modular la producción de diferentes mediadores inflamatorios como TNF-α vía receptor, disminuyendo de esta forma el tono inflamatorio a nivel celular y la sobreexpresión de COX-2 [28][29][30] .…”

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude

“…Melatonin decreased cellular density, α-actin of the media, and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk Polglase et al 98 Umbilical artery ligation Melatonin administration reduced secondary septal crest density and altered elastin deposition Gonzalez-Candia et al 102 Fetal/neonatal chronic hypoxia…”