Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha, China.
Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Oxid Med Cell Longev. 2020 Feb 13;2020:6978784. doi: 10.1155/2020/6978784. eCollection 2020.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H inhalation. Furthermore, H inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) and sirtuin 1 (SIRT1) and reversed the protectivity of H against OGD/R-induced cell death. These findings suggest that H augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1 and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H inhalation had better protective effects on HIBI. These effects of H may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H-mediated protection through the MAPK/HO-1/PGC-1 pathway. Our results support further assessment of H as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.
新生儿缺氧缺血性脑病（HIE）是新生儿死亡的主要原因，目前尚无有效的治疗方法。氢气（H）气体的最新进展为缺血再灌注损伤提供了一种有前途的治疗方法；然而，这种方法对 HIE 的影响仍然存在争议。我们在新生大鼠缺氧缺血性脑损伤（HIBI）模型中评估了 H 气体对 HIE 的治疗作用及其潜在的分子机制。H 气体吸入可显著减轻神经元损伤，有效改善新生 HIBI 大鼠的早期神经预后，并改善成年大鼠的学习和记忆能力。这种保护作用与持续 H 气体吸入的起始时间和持续时间有关。此外，H 气体吸入降低了 Bcl-2 相关 X 蛋白（BAX）和半胱天冬酶-3 的表达，同时促进了 Bcl-2、核因子红细胞 2 相关因子 2 和血红素加氧酶-1（HO-1）的表达。H 气体在氧葡萄糖剥夺/再灌注（OGD/R）神经生长因子分化的 PC12 细胞中激活细胞外信号调节激酶和 c-Jun N 端蛋白激酶，并使磷酸化 p38 丝裂原活化蛋白激酶（MAPK）去磷酸化。MAPK 抑制剂阻断了 H 诱导的 HO-1 表达。HO-1 小干扰 RNA 降低了过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC-1）和 Sirtuin 1（SIRT1）的表达，并逆转了 H 对 OGD/R 诱导的细胞死亡的保护作用。这些发现表明，H 通过激活 MAPK 信号通路增强细胞抗氧化防御能力，导致 HO-1 表达，并随后上调 PGC-1 和 SIRT1 的表达。因此，上调可保护 NGF 分化的 PC12 细胞免受 OGD/R 诱导的氧化细胞毒性。总之，H 气体吸入对 HIBI 新生大鼠具有保护作用。早期开始并延长 H 气体吸入对 HIBI 有更好的保护作用。H 的这些作用可能与抗氧化、抗凋亡和抗炎反应有关。HO-1 通过 MAPK/HO-1/PGC-1 途径在 H 介导的保护中发挥重要作用。我们的研究结果支持进一步评估 H 作为一种可能的治疗方法，用于涉及氧化应激和细胞凋亡的神经疾病。
