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

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-1 alpha (HIF-1 alpha) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-kappa B). Lethal ischemia (LI) without IPC increased expressions of HIF-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B 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-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1 alpha inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1 alpha, VEGF, and p-I kappa B-alpha expressions. This study suggests that IPC increases HIF-1 alpha expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-kappa B activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury.