Abstract
Hypoxic-ischemic encephalopathy (HIE) resulting from asphyxia is the most common cause of neonatal brain damage and results in significant neurological sequelae, including cerebral palsy. The current therapeutic interventions are extremely limited in improving neonatal outcomes. The present study tests the hypothesis that the suppression of endogenous glucocorticoid receptors (GRs) in the brain increases hypoxic-ischemic (HI) induced neonatal brain injury and worsens neurobehavioral outcomes through the promotion of increased inflammation. A mild HI treatment of P9 rat pups with ligation of the right common carotid artery followed by the treatment of 8% O2 for 60 min produced more significant brain injury with larger infarct size in female than male pups. Intracerebroventricular injection of GR siRNAs significantly reduced GR protein and mRNA abundance in the neonatal brain. Knockdown of endogenous brain GRs significantly increased brain infarct size after HI injury in male, but not female, rat pups. Moreover, GR repression resulted in a significant increase in inflammatory cytokines TNF-α and IL-10 at 6 h after HI injury in male pups. Male pups treated with GR siRNAs showed a significantly worsened reflex response and exhibited significant gait disturbances. The present study demonstrates that endogenous brain GRs play an important role in protecting the neonatal brain from HI induced injury in male pups, and suggests a potential role of glucocorticoids in sex differential treatment of HIE in the neonate.
Highlights
Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal brain damage and occurs in three per thousand live term births and six per thousand premature infant births [1,2,3]
The goal of this study was to investigate the role of the glucocorticoid receptors (GRs) in the pathogenesis of brain injury caused by asphyxia in near-term infants
In a full-term newborn, the GR is diffusely expressed throughout the whole brain and the expression level is highest at birth, when the HPA-axis becomes active and is critical to a newborn’s immediate survival [23]
Summary
Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal brain damage and occurs in three per thousand live term births and six per thousand premature infant births [1,2,3]. GR plays a critical role in the development of infant birth weight, muscle tone, and its requirement for proper neuronal system maturation [6]. Neonatal hypoxia causes a surge in plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels, and long-term reprogramming of the HPA-axis [8,9]. We demonstrated that gestational hypoxia downregulated the GR in the developing brain via epigenetic mechanisms, rendering the neonatal brain vulnerable to hypoxic-ischemic injury by decreasing the GR-mediated neuroprotection [10,11]. The role of endogenous GR in the immature brain in the pathological setting of HI injury remains unknown
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