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Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia

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Abstract

Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic insults by specific mechanisms. We tested the hypothesis that IPC attenuates post-ischemic neuronal death in the gerbil hippocampal CA1 region (CA1) throughout hypoxia inducible factor-1α (HIF-1α) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-κB). Lethal ischemia (LI) without IPC increased expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) in CA1 pyramidal neurons at 12 h and/or 1-day post-LI; thereafter, their expressions were decreased in the CA1 pyramidal neurons with time and newly expressed in non-pyramidal cells (pericytes), and the CA1 pyramidal neurons were dead at 5-day post-LI, and, at this point in time, their immunoreactivities were newly expressed in pericytes. In animals with IPC subjected to LI (IPC/LI)-group), CA1 pyramidal neurons were well protected, and expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1α inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1α, VEGF, and p-IκB-α expressions. This study suggests that IPC increases HIF-1α expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-κB activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury.

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Acknowledgments

The authors would like to thank Mr. Seung Uk Lee for his technical help in this study. This work was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (NRF-2015M3A9B6066835), by the National Research Foundation of Korea (NRF-2013M3A9B6046563), which was funded by the Ministry of Science, ICT, and Future Planning, and by Bio-Synergy Research Project (NRF-2015M3A9C4076322) of the Ministry of Science, ICT and Future Planning through the National Research Foundation.

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Authors and Affiliations

  1. Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea

    Jae-Chul Lee, In Hye Kim, Jeong Hwi Cho, Tae-Kyeong Lee & Moo-Ho Won

  2. Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeollabuk-do, 54596, South Korea

    Hyun-Jin Tae

  3. Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea

    Joon Ha Park, Ji Hyeon Ahn & Soo Young Choi

  4. Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China

    Hui Chen Bai

  5. Department of Physiology, College of Medicine, Hallym University, Chuncheon, 24252, South Korea

    Bich-Na Shin

  6. Pharmacology & Toxicology Department, Shinpoong Pharmaceutical Co., Ltd., Ansan, 15610, South Korea

    Geum-Sil Cho

  7. Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University, Gangneung, 25457, South Korea

    Dae Won Kim

  8. Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252, South Korea

    Il Jun Kang

  9. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea

    Young-Guen Kwon

  10. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea

    Young-Myeong Kim

  11. Department of Pediatrics, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chunchen, 24253, South Korea

    Eun Joo Bae

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Jae-Chul Lee and Hyun-Jin Tae contributed equally to this article.

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Lee, JC., Tae, HJ., Kim, I.H. et al. Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia. Mol Neurobiol 54, 6984–6998 (2017). https://doi.org/10.1007/s12035-016-0219-2

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