Evaluation of preconditioning treatments to protect near-pure cortical neuronal cultures from in vitro ischemia induced acute and delayed neuronal death

Meloni, Bruno P.; Majda, Bernadette T.; Knuckey, Neville W.

doi:10.1016/s0006-8993(01)03361-3

Cited by 31 publications

(24 citation statements)

References 37 publications

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“…Moreover, they showed that treatment with a NMDA receptor antagonist, MK801, during OGD preconditioning completely blocked preconditioning-induced ERK1/2 phosphorylation and also blocked subsequent ischemic tolerance. In contrast, it has also been reported that preconditioning treatment with MK801 induces tolerance against subsequent lethal OGD in near-pure primary cultured cortical neurons (Meloni et al, 2002). Although we observed that MK801 provided neuroprotection against lethal 3-h OGD-induced cell death dosedependently, application of MK801 during OGD preconditioning did not block ischemic tolerance in our study (data not shown).…”

Section: Discussioncontrasting

confidence: 88%

“…Other than anoxia or hypoxia, ischemic tolerance can be induced by diverse preconditioning stimuli such as oxidative stress, hypothermia, heat shock, anesthetics, excitotoxins, cytokines, metabolic inhibitors (Meloni et al, 2002). However, the signaling mechanism responsible for these diverse forms of preconditioning remains mostly a mystery.…”

Section: Discussionmentioning

confidence: 99%

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Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro

et al. 2011

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Ischemic preconditioning can provide protection to neurons from subsequent lethal ischemia. The molecular mechanisms of neuronal ischemic tolerance, however, are still not well-known. The present study, therefore, examined the role of MAPK and PI3K/Akt pathways in ischemic tolerance induced by preconditioning with sublethal oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. Ischemic tolerance was simulated by preconditioning of the neurons with sublethal 1-h OGD imposed 12 h before lethal 3-h OGD. The time-course studies of relative phosphorylation and expression levels of ERK1/2, JNK and p38 MAPK showed lack of their involvement in ischemic tolerance. However, there were significant increases in Akt phosphorylation levels during the reperfusion period following preconditioned lethal OGD. In addition, Bcl-2 associated death promoter (Bad) and GSK-3β were also found to be inactivated during that reperfusion period. Finally, treatment with an inhibitor of PI3K, wortmannin, applied from 15 min before and during lethal OGD abolished not only the preconditioning-induced neuroprotection but also the Akt activation. Concomitant with blockade of the Akt activation, PI3K inhibition also resulted in activation of Bad and GSK-3β. The results suggest that ischemic tolerance induced by sublethal OGD preconditioning is primarily mediated through activation of the PI3K/Akt pathway, but not the MAPK pathway, in rat cortical neurons.

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro

et al. 2011

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“…The half-life of HIF-1α is very short, only about 5 min [32]. How cells sense low oxygen levels to elicit HIF-1α induction and stabilization and how HIF-1 α is involved in H/I preconditioning protection is not clear.…”

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confidence: 99%

Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons

Chang

Jiang

Zhao

et al. 2008

Neuroscience Letters

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Neuroprotection against neonatal ischemic brain injury may be achieved by hypoxic or ischemic preconditioning, a phenomenon that occurs when a brief exposure to sublethal hypoxia or ischemia renders the brain less vulnerable to subsequent (24-48 h later) prolonged and injurious ischemia [13,17,20]. The molecular mechanisms for this ischemic tolerance are not fully understood. We and others have shown that hypoxia-inducible factor 1 (HIF-1), a transcription factor sensitive to regulation by hypoxia/ischemia (H/I), plays a pivotal role in H/I preconditioning protection in the neonatal brain [5,6,24]. HIF-1, a heterodimeric complex of HIF-1α and HIF-1β, is a key regulator for induction of genes that increase blood flow, stimulate glucose and lactate delivery to cells, enhance metabolism and promote growth and repair in neurons and blood vessels [36]. These genes include erythropoietin [38], which increases the proliferation of erythrocytes; tyrosine hydroxylase, which is necessary for the synthesis of the neurotransmitter dopamine in the carotid bodies; the angiogenic factor vascular endothelial growth factor, which stimulates growth of new capillaries [11,25,38] and endothelial nitric oxide synthase and heme oxygenase-1 (HO-1) [27], which are potent vasodilatory substances that augment perfusion of hypoxic tissue. At the cellular level, hypoxia and HIF-1 induce the expression of virtually all glycolytic enzymes, including phosphoglycerate kinase-1, enolase 1, and lactate dehydrogenase-1 [14,37]. Both HIF-1α and HIF-1β are constitutively expressed in cells and tissues, but the α subunit protein is rapidly degraded by prolyl hydroxylase-dependent proteasomal system under normoxic conditions Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The aim of this study was to investigate whether brief ischemia (OGD) or low dose exogenous H 2 O 2 could trigger HIF-1 α expression and thereby, contribute to H/I preconditioning protection in the immature brain. To test this hypothesis, we used 6-8 days in vitro (DIV) primary cortical neurons from embryonic day 16 (E16) CD1 mouse brains and preconditioned them with either 10 min of OGD or exogenous H 2 O 2 at doses from 5-50 μM. HIF-1α protein levels were assessed at different time points after preconditioning. Cells were exposed to 2 h of OGD 24 h after preconditioning, and cell viability was determined 24 h thereafter. NIH Public AccessAll animal experiments were approved by the Institutional Animal Care and Use Committee at the University of California San Francisco. Cortical tissue was dissected from the brains of E16 CD1 mice (Charles ...

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“…Hypoxic preconditioning (HPC), 1 for example, caused by lowering the oxygen content or by combined oxygen and glucose deprivation, protects against subsequent hypoxic injury (4,7,8,10). However, a recent study failed to show neuronal protection with HPC treatment (11), suggesting that the neuronal response to preconditioning may vary depending on neuronal situation and involve complex mechanisms. These molecular mechanisms remain unclear, especially with regard to intracellular signal transduction.…”

mentioning

confidence: 99%

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

Chieh

Qian

Ghassemi

et al. 2005

Journal of Biological Chemistry

150

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The detrimental effect of severe hypoxia (SH) on neurons can be mitigated by hypoxic preconditioning (HPC), but the molecular mechanisms involved remain unclear, and an understanding of these may provide novel solutions for hypoxic/ischemic disorders (e.g. stroke). Here, we show that the ␦-opioid receptor (DOR), an oxygen-sensitive membrane protein, mediates the HPC protection through specific signaling pathways. Although SH caused a decrease in DOR expression and neuronal injury, HPC induced an increase in DOR mRNA and protein levels and reversed the reduction in levels of the endogenous DOR peptide, leucine enkephalin, normally seen during SH, thus protecting the neurons from SH insult. The HPC-induced protection could be blocked by DOR antagonists. The DOR-mediated HPC protection depended on an increase in ERK and Bcl 2 activity, which counteracted the SH-induced increase in p38 MAPK activities and cytochrome c release. The cross-talk between ERK and p38 MAPKs displays a "yinyang" antagonism under the control of the DOR-G protein-protein kinase C pathway. Our findings demonstrate a novel mechanism of HPC neuroprotection (i.e. the intracellular up-regulation of DOR-regulated survival signals).Neuronal death as a result of neuronal injury following hypoxic/ischemic insults, such as stroke, is an irreversible process that leads to long term neurological deficit. The prevention of neuronal injury is therefore critical in rescuing the brain from neurological disaster. However, clinical strategies that may help mitigate the effects of hypoxic/ischemic injury are still very limited.One strategy that has been shown to provide effective protection from harmful stress is known as preconditioning. This involves transient, but sublethal, exposure to a stress, resulting in enhanced cellular resistance to subsequent severe stress. It was initially demonstrated in the heart (1) and subsequently found to work in other organ beds (2). The effects of preconditioning have been widely studied in the whole brain (3, 4), as well as in vitro in brain slices (5, 6) and neuronal cultures (7-9). Most studies to date have shown the beneficial effects of preconditioning on rescuing neurons from cell injury in response to subsequent severe insults. Hypoxic preconditioning (HPC), 1 for example, caused by lowering the oxygen content or by combined oxygen and glucose deprivation, protects against subsequent hypoxic injury (4,7,8,10). However, a recent study failed to show neuronal protection with HPC treatment (11), suggesting that the neuronal response to preconditioning may vary depending on neuronal situation and involve complex mechanisms. These molecular mechanisms remain unclear, especially with regard to intracellular signal transduction. In this study, we demonstrated that, in neurons in culture, HPCinduced neuroprotection is dependent on specific factors and that the effect is mediated by intracellular up-regulation of ␦-opioid receptor (DOR)-regulated survival signals, which suppress the increased activity of intracellular death s...

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Evaluation of preconditioning treatments to protect near-pure cortical neuronal cultures from in vitro ischemia induced acute and delayed neuronal death

Cited by 31 publications

References 37 publications

Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro

Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro

Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons

Oxygen-sensitive δ-Opioid Receptor-regulated Survival and Death Signals

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