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

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.

• Authors: Jae-Chul Lee, Hyun-Jin Tae, In Hye Kim, Jeong Hwi Cho, Tae-Kyeong Lee, Joon Ha Park, Ji Hyeon Ahn, Soo Young Choi, Hui Chen Bai, Bich-Na Shin, Geum-Sil Cho, Dae Won Kim, Il Jun Kang, Young-Guen Kwon, Young-Myeong Kim, Moo-Ho Won, Eun Joo Bae
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 54 Issue 9 Pg. 6984-6998 (11 2017) ISSN: 1559-1182 [Electronic] United States
• PMID: 27785755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-kappa B
• Vascular Endothelial Growth Factor A
• NF-KappaB Inhibitor alpha
• 2-Methoxyestradiol

Topics

• 2-Methoxyestradiol
• Animals
• CA1 Region, Hippocampal (pathology)
• Gerbillinae
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Ischemic Attack, Transient (metabolism, pathology)
• Ischemic Preconditioning
• Male
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Neurons (metabolism)
• Neuroprotection
• Pyramidal Cells (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)