Institute of Neurosciences and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University and Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, 510260, P. R. China.
Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Road, 2030B, Atlanta, GA, 30322, USA.
Cell Death Dis. 2018 May 25;9(6):635. doi: 10.1038/s41419-018-0656-0.
Hypoxic postconditioning (HPC) is an innovative neuroprotective strategy with cytoprotective effects on the hippocampal neurons against transient global cerebral ischemia (tGCI) in adult rats. However, its molecular mechanisms have not yet been adequately elucidated. Neuroglobin (Ngb) is an endogenous neuroprotectant with hypoxia-inducible property, and its role in experimental stroke has been increasingly attractive. Hence, the purpose of this study is to explore the involvement of Ngb in HPC-mediated neuroprotection and to further investigate its underlying molecular mechanism. We found that HPC increased Ngb expression in CA1 subregion after tGCI. Also, the inhibition of Ngb expression with Ngb antisense oligodeoxynucleotide (AS-ODNs) eliminated the neuroprotective effect mediated by HPC, whereas overexpression of Ngb ameliorated neuronal damage in CA1 after tGCI, indicating that HPC conferred neuroprotective effects via upregulation of Ngb. We further showed that HPC increased the membranous level of Na/K ATPases β1 subunit (Atp1b1) in CA1 after tGCI. Furthermore, we demonstrated that Ngb upregulation in CA1 after HPC maintained the membranous level of Atp1b1 through Ngb-Atp1b1 interaction and reduced the glutathionylation of membranous Atp1b1 via suppression of reactive oxygen species (ROS), ultimately preserving the activity of NKA. Taken together, these data indicate that Ngb is involved in the neuroprotection of HPC against tGCI via maintenance of NKA activity in the hippocampal CA1.
缺氧后处理（HPC）是一种创新的神经保护策略，对成年大鼠短暂全脑缺血（tGCI）时的海马神经元具有细胞保护作用。然而，其分子机制尚未得到充分阐明。神经球蛋白（Ngb）是一种内源性神经保护剂，具有缺氧诱导特性，其在实验性中风中的作用越来越受到关注。因此，本研究旨在探讨 Ngb 在 HPC 介导的神经保护中的作用，并进一步研究其潜在的分子机制。我们发现 tGCI 后 HPC 增加了 CA1 区的 Ngb 表达。此外，用 Ngb 反义寡核苷酸（AS-ODNs）抑制 Ngb 表达消除了 HPC 介导的神经保护作用，而过表达 Ngb 改善了 tGCI 后 CA1 的神经元损伤，表明 HPC 通过上调 Ngb 发挥神经保护作用。我们进一步表明，HPC 增加了 tGCI 后 CA1 中的 Na/K ATPases β1 亚基（Atp1b1）的膜水平。此外，我们证明 HPC 后 CA1 中的 Ngb 上调通过 Ngb-Atp1b1 相互作用维持了 Atp1b1 的膜水平，并通过抑制活性氧（ROS）减少了膜结合 Atp1b1 的谷胱甘肽化，最终维持了 NKA 的活性。总之，这些数据表明，Ngb 通过维持海马 CA1 中 NKA 的活性参与了 HPC 对 tGCI 的神经保护作用。
