Hypoxia-Inducible Factor-1α Protects Cultured Cortical Neurons from Lipopolysaccharide-Induced Cell Death via Regulation of NR1 Expression

Abstract

Inflammation is involved in some neurodegenerative disorders. NMDA glutamate receptors play an important role in neuronal development. Here, we show that NR1 expression in the cerebral cortex and primary neurons of rats was upregulated after lipopolysaccharide (LPS) treatment. This increase in NR1 expression was considered to be strongly associated with hypoxia-inducible factor-1␣ (HIF-1␣) activation because the treatment of primary neurons with either echinomycin or small interfering RNA (siRNA) targeting HIF-1␣ could block NR1 expression. HIF-1␣ could be induced by an increase in the translational efficiency of the cells. After this, it was transported into the nucleus where it bound to the NR1 promoter and regulated the induction of NR1 transcriptional activity by LPS. LPS injection into the prefrontal cortex caused neuronal death, and this condition was aggravated by intracerebroventricular injection of echinomycin. Furthermore, knockdown of HIF-1␣ and NR1 by the appropriate siRNAs reduced the neurite outgrowth and viability of the primary neurons. These results suggest that NR1 expression is regulated by HIF-1␣ and plays a protective role in neurons during LPS challenge.

Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl- d -Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure

“…The NMDA-NR 1 promoter sequence has at least one known HIF-1 transcription complex binding site 25 . This suggests that the HIF-1 transcription complex may bind to the NMDA-NR 1 promoter and increase transcription of NMDA-NR 1 .…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Tbr-1 is a neuron-specific T-box factor (Hsueh et al, 2000) that may play a role in neurogenesis and induction of GluN1. GluN1 expression is subject to control by hypoxia-inducible factors that function under stress conditions, especially during hypoxia (Yeh et al, 2008). Based on GluN1 up-regulation after lipopolysaccharide injection into the prefrontal cortex and in cultured neurons, the predicted cis hypoxia response elements were localized within the Grin1 promoter.…”

Oxidative Stress Does Not Predispose Neuronal Cells to Changes in G Protein Coupled (Opioid) Receptor Gene Expression in Cortical B50 Neurons in Culture

“…This supports the finding that the longer the neurons stayed in the culture media in the experimental hypoxic groups, the greater the extent of the neuronal cell injuries and death (Francis and Wei 2010;Du et al 2012;Prentice et al 2012). A possible explanation for this phenomenon is that prolonged hypoxia may cause a significant release and accumulation of endogenous glutamate which causes glutamate-induced toxicity and hence death of the cells (Nyakas et al 1996;Yeh et al 2008;Francis and Wei 2010).…”

“…It has been observed that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to the activation of pro-apoptotic genes (Gibson and Huang 2002;Du et al 2012). Hypoxia-induced oxidative stress can cause neurite retraction leading to neurodegeneration and neuronal loss similar to that found in Alzheimer's disease (Banasiak et al 2000;de la Monte et al 2000;Yeh et al 2008;Prentice et al 2011;López-Hernández et al 2012).…”

“…Severe hypoxia has been shown to induce apoptotic cell death in developing brain neurons whereas mild hypoxia has been demonstrated to stimulate neurogenesis (Bossenmeyer-Pourie et al 2002;Yeh et al 2008). Hypoxia threatens brain function throughout the entire life span and although the physiological consequences of brain hypoxia are well documented, the molecular mechanisms involved in these processes are still not well understood (Rossler et al 2001;Zhu et al 2005;Semenza 2006, Semenza 2007.…”