Maternal lactoferrin supplementation prevents mitochondrial and redox homeostasis dysfunction, and improves antioxidant defenses through Nrf2 and UCP2 signaling after neonatal hypoxia-ischemia

Abstract

Neonatal hypoxia-ischemia (HI) is a major cause of mortality and neurological impairments in infants. Main HI-induced pathological mechanisms include mitochondrial dysfunction and oxidative stress due to insufficient oxygen and energetic substrates to the nervous cells. Bovine lactoferrin (Lf) has demonstrated neuroprotective effects in several experimental models of neonatal brain injury in rodents, however its mechanisms remain unclear. This study aimed to evaluate the early impact of maternal dietary supplementation with Lf on redox and hippocampal mitochondrial function following neonatal HI. From postnatal day 6 (PND6), pregnant Wistar rats were fed with a diet supplemented with Lf (1 g/kg) or with an isocaloric control diet until offspring euthanasia. At PND7, pups of both sexes were subjected to experimental HI through the occlusion of the right common carotid artery followed by 60 min of hypoxia (8 % oxygen). Lf prevented HI-induced increased levels of DCFH and lipoperoxidation in hippocampus. Furthermore, Lf enhanced antioxidant defenses including SOD, GPx, and GSH, counteracting HI-induced oxidative stress. HI injury altered the activities of enzymes in the mitochondrial respiratory chain and increased the mitochondrial membrane potential. Both effects were counteracted by Lf supplementation. Lactoferrin prevented oxidative stress and to restored mitochondrial function by upregulating Nrf2 and UCP2 expression following experimental HI. Our results show that even a shorter period of Lf delivery to rat pups is able to improve hippocampal response to neonatal hypoxia-ischemia, reversing initial mechanisms of damage in the cascade of HI injury.