Repression of the Glucocorticoid Receptor Increases Hypoxic-Ischemic Brain Injury in the Male Neonatal Rat

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.

TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice

“…Besides, the silencing efficiency of TREM2 siRNA upon local injection in mouse brain is also a concern in our research process. Recent studies and our present study have demonstrated effectiveness of local knockdown of genes using siRNAs in the brain [56,57]. However, the time window and tissue area of siRNA are very limited, because of the poor intracellular uptake and low blood stability of siRNA.…”

Role of CRF and the hypothalamic‐pituitary‐adrenal axis in stroke: revisiting temporal considerations and targeting a new generation of therapeutics

“…Separately, 129/SV mice that were exposed to chronic variable stress for 28 days prior to cerebral ischaemia induced by 30 min of MCAO demonstrated elevated heart rates, decreased vascular vasodilation, increased superoxide and suppressed endothelial nitric oxide synthase compared to control animals. Again, these effects were prevented by 28‐day pretreatment with mifepristone [189].…”

Risk Factors and Nomogram for the Prediction of Intracranial Hemorrhage in Very Preterm Infants

“…ACS prevents NRDS and reduces brain injury due to hypoxia, glucocorticoids exert anti-in ammatory effects to inhibit the in ammatory cascade response, and glucocorticoids promote the developmental maturation of oligodendrocytes and endothelial cells to exert neuroprotective effects. In experimental animal studies, glucocorticoids promote the maturation of capillaries in the murine choroid plexus [22] . One study reported that the timing of the last dose of corticosteroid before delivery also in uences risk for brain injury, with signi cantly reduced risk observed when the interval since the last dose is greater than 48 hours, compared with less than 24 hours [23] .…”