Lawrence D. Longo, MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Int J Mol Sci. 2019 Jul 16;20(14):3493. doi: 10.3390/ijms20143493.
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% O 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.
缺氧缺血性脑病（HIE）是由于窒息导致的最常见的新生儿脑损伤病因，并导致严重的神经后遗症，包括脑瘫。目前的治疗干预措施在改善新生儿结局方面的效果非常有限。本研究通过检测内源性糖皮质激素受体（GR）在大脑中的抑制作用是否增加缺氧缺血（HI）诱导的新生儿脑损伤，并通过促进炎症增加来恶化神经行为结果，以此验证假说。对 P9 日龄幼鼠右侧颈总动脉结扎后给予 8% O2 处理 60 min 产生轻度 HI 处理，结果发现雌性幼鼠比雄性幼鼠的脑损伤更严重，梗死面积更大。脑室注射 GR siRNAs 可显著降低新生鼠大脑中的 GR 蛋白和 mRNA 丰度。内源性脑 GR 敲低显著增加了雄性而非雌性幼鼠 HI 损伤后的脑梗死面积。此外，GR 抑制导致雄性幼鼠 HI 损伤后 6 h 时炎症细胞因子 TNF-α和 IL-10 显著增加。用 GR siRNAs 处理的雄性幼鼠表现出明显恶化的反射反应，并表现出明显的步态障碍。本研究表明，内源性脑 GR 在保护雄性幼鼠免受 HI 诱导的损伤中发挥重要作用，并提示糖皮质激素在新生儿 HIE 的性别差异治疗中可能发挥作用。
