HIF-1α is neuroprotective during the early phases of mild hypoxia in rat cortical neurons

López-Hernández, Beatriz; Posadas, Inmaculada; Podlesniy, Petar; Abad, Maria Alba; Trullás, Ramón; Ceña, Valentı́n

doi:10.1016/j.expneurol.2011.11.040

Cited by 41 publications

(31 citation statements)

References 47 publications

(37 reference statements)

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“…Depletion of HIF-1α in the mouse brain and in neuronal cell cultures causes increased cell damage and lower survival rate after cerebral ischemia (Baranova et al, 2007). In rat cortical neurons, HIF-1α appears to play a protective role in early steps of responses to mild hypoxia (Lopez-Hernandez et al, 2012). HIF-1α has recently been shown to regulate prion protein expression in hippocampal neuronal cells to protect from cell damage (Jeong et al, 2012).…”

Section: Key Molecules Involvedmentioning

confidence: 99%

Neuronal Responses to Physiological Stress

Kagias¹,

Nehammer²,

Pocock³

2012

Front. Gene.

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Physiological stress can be defined as any external or internal condition that challenges the homeostasis of a cell or an organism. It can be divided into three different aspects: environmental stress, intrinsic developmental stress, and aging. Throughout life all living organisms are challenged by changes in the environment. Fluctuations in oxygen levels, temperature, and redox state for example, trigger molecular events that enable an organism to adapt, survive, and reproduce. In addition to external stressors, organisms experience stress associated with morphogenesis and changes in inner chemistry during normal development. For example, conditions such as intrinsic hypoxia and oxidative stress, due to an increase in tissue mass, have to be confronted by developing embryos in order to complete their development. Finally, organisms face the challenge of stochastic accumulation of molecular damage during aging that results in decline and eventual death. Studies have shown that the nervous system plays a pivotal role in responding to stress. Neurons not only receive and process information from the environment but also actively respond to various stresses to promote survival. These responses include changes in the expression of molecules such as transcription factors and microRNAs that regulate stress resistance and adaptation. Moreover, both intrinsic and extrinsic stresses have a tremendous impact on neuronal development and maintenance with implications in many diseases. Here, we review the responses of neurons to various physiological stressors at the molecular and cellular level.

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Section: Key Molecules Involvedmentioning

confidence: 99%

Neuronal Responses to Physiological Stress

Kagias¹,

Nehammer²,

Pocock³

2012

Front. Gene.

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“…However, this neuroprotective effect seems to be transitory. For instance, HIF‐1α protects neurons from apoptosis during the early phase of chemical hypoxia or from mild hypoxia but, under prolonged hypoxia, the neuroprotective effect was lost and neurons eventually die from apoptosis (Posadas et al ., ; Lopez‐Hernandez et al ., ). These findings suggest that additional mechanisms are involved in determining neuronal survival or death at the later stages of hypoxia.…”

Section: Introductionmentioning

confidence: 99%

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

López-Hernández

Ceña

Posadas

2015

British J Pharmacology

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BACKGROUND AND PURPOSEHypoxia inducible factor-1 (HIF-1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum (ER) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia-induced neuronal death and analysed the relationship between ER stress and the HIF-1 pathways. EXPERIMENTAL APPROACHCultures of rat cortical neurons were exposed to chemical hypoxia induced by 200 μM CoCl2, and its effect on neuronal viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and counting apoptotic nuclei. Protein levels were determined by Western blot analysis. RT-PCR was performed to analyse the content and the t1/2 of HIF-1α mRNA. KEY RESULTSChemical hypoxia induced neuronal apoptosis in a time-dependent manner and activated the ER stress PRK-like endoplasmic reticulum kinase (PERK)-dependent pathway. At later stages, chemical hypoxia increased the expression of the C/EBP homologous protein (CHOP) and caspase 12 activity. CoCl2 reduced HIF-1α mRNA t1/2 leading to a decrease in HIF-1α mRNA and protein content, simultaneously activating the ER stress PERK-dependent pathway. Salubrinal, a selective inhibitor of phospho-eIF2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t1/2 of HIF-1α mRNA and the levels of HIF-1α protein. Knocking down HIF-1α blocked the neuroprotective effects of salubrinal. CONCLUSIONS AND IMPLICATIONSNeuronal apoptosis induced by chemical hypoxia is a process regulated by HIF-1α stabilization early on and by ER stress activation at later stages. Our data also suggested that HIF-1α levels were regulated by ER stress. AbbreviationsATF, activating transcription factor; CHOP, C/EBP homologous protein; ddH2O, double distillate water; DIV, days in vitro; eIF2α, initiation elongation factor 2α; EPO, erythropoietin; ER, endoplasmic reticulum; GLUT1, glucose transporter 1; GRP-78/Bip, glucose-regulated protein 78; HIF-1, hypoxia inducible factor-1; IRE1α, inositol-requiring 1 α; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PERK, PRK-like endoplasmic reticulum kinase; TMRM, tetramethylrhodamine methyl ester BJP British Journal of Pharmacology

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“…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).…”

Section: Introductionmentioning

confidence: 88%

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

Ibegbu

Mullaney

Fyfe

et al. 2012

International Journal of Human Genetics

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Oxidative stress adversely affects neuronal cells in which they may die when oxygen supply is reduced or eliminated and opioid receptor agonists elicit several central nervous system effects. The aim of this study was to evaluate the effect of oxidative stress on opioid receptor gene expression in cortical B50 cells. The cells were cultured in normoxia, hypoxia and treated with opioid agonists; DAMGO (µ), DSLET (δ) and 441 (κ) for 48 hours after 48 hours of initial culture at dose of 10µM, 50µM and 100µM. The level of mu opioid receptor mRNA was assessed using RT-PCR. The results show that oxidative stress induced changes in B50 cells in hypoxia while mu opioid mRNA levels showed no change. The results show that B50 cells are susceptible to damage by oxidative stress and opioid agonist treatments showed no change in the level of mu opioid receptor gene expression in B50 cells.

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HIF-1α is neuroprotective during the early phases of mild hypoxia in rat cortical neurons

Cited by 41 publications

References 47 publications

Neuronal Responses to Physiological Stress

Neuronal Responses to Physiological Stress

The endoplasmic reticulum stress and the HIF‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia

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

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