Abstract
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.
Highlights
Transient global cerebral ischemia may result from cardiac arrest, serious hypertension, asphyxia, shock, or brain injuries, etc
The upregulation of Ngb induced by Hypoxic postconditioning (HPC) in the hippocampal CA1 contributed to the neuroprotection against Transient global cerebral ischemia (tGCI) Immunohistochemical assay was conducted to examine the distribution of Ngb in the brain
The quantitative analysis showed that the number of Ngb-positive neuron-like cells in CA1 decreased at 26 h, increased to the basal expression level at 50 h, and significantly reduced at 168 h after tGCI, while kept increasing consistently in the HPC groups (Fig. 1B)
Summary
Transient global cerebral ischemia (tGCI) may result from cardiac arrest, serious hypertension, asphyxia, shock, or brain injuries, etc. The hippocampal CA1 pyramidal neurons are essential for cognitive functions and are selectively vulnerable to tGCI1,2. Tremendous work has been directed to the molecular basis of the selective vulnerability of CA1, until now, there have been tGCI remain poorly understood. Official journal of the Cell Death Differentiation Association. Wen et al Cell Death and Disease (2018)9:635. Neuroglobin (Ngb) was originally identified in the human and the mouse brain. It is predominantly expressed in the neurons and the astrocytes[9]. Ngb may serve as a hypoxic sensor and initiate signal transduction involving in oxidative and hypoxic pathway, cell survival/apoptotic pathway, and ATP pathway in neuronal cells[11]. It has been proposed that the neuroprotection of Ngb at the mitochondrial level is related to its activities to scavenge a variety of free radicals, and to its ability to interact with cytochrome C (Cyc) in the mitochondria[12,13]
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