Hypoxic-ischemic brain damage (HIBD) is a frequent cause of mortality and neurological handicaps in infants and children worldwide. To understand better the pathogenesis and management of HIBD, we established a HIBD model by common carotid artery ligation followed by systemic hypoxia in neonatal rats, and in other studies induced neuronal death in rat pheochromocytoma (PC12) cells by 12 h of oxygen-glucose deprivation (OGD). The level of KPNA3 declined in rats following experimental HIBD and in PC12 cells following OGD. KPNA3 overexpression protected neonatal rats against HIBD and PC12 cells against OGD-induced cell death. KPNA3 demonstrated to be the target of miR-134-5p could be activated by the transcriptional factor CCAAT/enhancer binding protein alpha (C/EBPα). The expression of miR-134-5p and C/EBPα was elevated in rats following experimental HIBD and in PC12 cells following OGD. In the parallel experiments, C/EBPα knockdown and miR-134 inhibition protected against HIBD pathology in neonatal rats and against OGD-induced neuronal death in PC12 cells. These findings reveal that the C/EBPα/miR-134-5p/KPNA3 axis mediates hypoxic-ischemic brain damage and neuronal death, thus presenting a potential therapeutic target for the treatment of human newborns at risk for HIBD.

缺氧缺血性脑损伤 (HIBD) 是全球婴儿和儿童死亡和神经障碍的常见原因。为了更好地了解 HIBD 的发病机制和管理，我们通过颈总动脉结扎，然后在新生大鼠全身缺氧建立 HIBD 模型，并在其他研究中通过 12 小时的氧-葡萄糖剥夺诱导大鼠嗜铬细胞瘤 (PC12) 细胞的神经元死亡(OGD)。实验性 HIBD 后大鼠和 OGD 后 PC12 细胞中 KPNA3 的水平下降。KPNA3 过表达保护新生大鼠免受 HIBD 和 PC12 细胞对 OGD 诱导的细胞死亡的影响。被证明是 miR-134-5p 靶标的 KPNA3 可以被转录因子 CCAAT/增强子结合蛋白 α（C/EBPα）激活。实验性 HIBD 后大鼠和 OGD 后 PC12 细胞中 miR-134-5p 和 C/EBPα 的表达升高。在平行实验中，C/EBPα 敲低和 miR-134 抑制可防止新生大鼠的 HIBD 病理和 PC12 细胞中 OGD 诱导的神经元死亡。这些发现表明，C/EBPα/miR-134-5p/KPNA3 轴介导缺氧缺血性脑损伤和神经元死亡，从而为治疗有 HIBD 风险的人类新生儿提供了潜在的治疗靶点。