Neurochemical Research

, Volume 42, Issue 2, pp 501–512 | Cite as

Chronic Intermittent Hypobaric Hypoxia Pretreatment Ameliorates Ischemia-Induced Cognitive Dysfunction Through Activation of ERK1/2-CREB-BDNF Pathway in Anesthetized Mice

  • Jintian Wang
  • Shixiao Zhang
  • Huijuan Ma
  • Shijie Yang
  • Zhao Liu
  • Xiaolei Wu
  • Sheng Wang
  • Yi Zhang
  • Yixian Liu
Original Paper


Chronic intermittent hypobaric hypoxia (CIHH) has protective effects on heart and brain against ischemia injury through mobilizing endogenous adaptive mechanisms. However, whether CIHH prevents against cognitive impairment was not elucidated. The present study aimed to investigate the effect and mechanism of CIHH treatment on ischemia/reperfusion (IR)-induced cognitive dysfunction. Mice were randomly divided into 8 groups: Control, Sham, CIHH (simulating 5000 m high-altitude for 28 days, 6 h per day), IR (three 16-min occlusions of bilateral common carotid arteries interrupted by two 10-min intervals), CIHH + IR, PD98059 (inhibitor of MEK1/2) + CIHH + IR, PD98059 + Sham and PD98059 + IR group. Morris water maze and step-down passive avoidance tests were performed to evaluate the capability of learning and memory 1 month after ischemia. Thionine dyeing was to examine histological manifestations of pyramidal neurons in hippocampus CA1 region. Western blotting assay was for measurement of the protein expressions in ERK1/2-CREB-BDNF signaling pathway. There were a shorter escape latency and a longer percentage of time retaining in the target quadrant in Morris water maze test, fewer times of errors in the step-down avoidance test and a higher neuronal density of the hippocampal CA1 subfield in CIHH + IR group than in IR group. CIHH upregulated the expressions of BDNF, phosphorylated CREB, ERK1/2 and TrkB with or without ischemia. The protective effects of CIHH were abolished by PD98059 administration 15 min before ischemia. CIHH ameliorated ischemia-induced cognitive dysfunction through activation of ERK1/2-CREB-BDNF signaling pathway.


Chronic intermittent hypobaric hypoxia Cognitive dysfunction Ischemia/reperfusion Brain-derived neurotrophic factor Extracellular signal-regulated kinases Mouse 



This work was supported by Natural Science Foundation of Hebei Province, China (C2014206363) and Hebei Province Students innovative and entrepreneurial project (201510089016).

Author Contributions

Designed experiment and wrote manuscript: YL. Performed experiment: JW, ZL, XW. Analyzed data: HuijuanMa. Wrote manuscript: SZ. Reviewed and approved the final version of the manuscript: SW, YZ.

Compliance with Ethical Standards

Conflict of interest

Authors have no conflict of interest in this study.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jintian Wang
    • 1
  • Shixiao Zhang
    • 1
  • Huijuan Ma
    • 1
  • Shijie Yang
    • 3
  • Zhao Liu
    • 1
  • Xiaolei Wu
    • 1
  • Sheng Wang
    • 1
    • 2
  • Yi Zhang
    • 1
    • 2
  • Yixian Liu
    • 1
    • 2
  1. 1.Department of PhysiologyHebei Medical UniversityShijiazhuangChina
  2. 2.Hebei Collaborative Innovation Center for Cardio-Cerebrovascular DiseaseShijiazhuangChina
  3. 3.Department of UrologyThird Hospital of Hebei Medical UniversityShijiazhuangChina

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