Characterisation of neuronal cell death in acute and delayed in vitro ischemia (oxygen–glucose deprivation) models

Meloni, Bruno P.; Meade, Amanda J.; Kitikomolsuk, Derek; Knuckey, Neville W.

doi:10.1016/j.jneumeth.2010.11.023

Cited by 55 publications

(32 citation statements)

References 23 publications

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“…We therefore assessed the effect of oxygen/glucose shortage in 7 days in vitro (DIV) cortical neurons by exposing WT and PHD1 −/− cultures to two hours of oxygen-nutrient deprivation ( i.e . 0.1% O 2 in medium lacking glucose, glutamine and pyruvate) after which they were re-exposed to ambient air and nutrient-rich medium (an established in vitro model of brain ischemia in vivo (Koh and Choi, 1987; Meloni et al, 2011)). After 24 hours, neuronal cell death, quantified by measuring LDH release in the medium, was substantially reduced in PHD1 −/− neurons (Figure 2O).…”

Section: Resultsmentioning

confidence: 99%

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Quaegebeur

Segura

Schmieder³

et al. 2016

Cell Metabolism

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Summary The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network, nor to enhanced neurotrophin expression. Instead, PHD1−/− neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1−/− neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose from glycolysis. As a result, PHD1−/− neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a novel regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.

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Section: Resultsmentioning

confidence: 99%

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Quaegebeur

Segura

Schmieder³

et al. 2016

Cell Metabolism

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“…Beyond the classical programmed cell death pathways, apoptosis (type1) and autophagy (type2), necroptosis termed a newfound caspase-independent programmed necrotic mode. It has been demonstrated that the occurrence of these cell death modes participate in neural injury in TBI and ischemia models [3,5,[7][8][9][10]. NEC-1, identified as a specific inhibitor of receptorinteracting protein-1 kinase, effectively inhibits necroptosis [6,19].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies had proved that both apoptosis and autophagy participated in neuronal cell death and functional loss after TBI [3,5]. Recently, a caspases-independent programmed cell death pathway, necroptosis, showed to be involved in ischemic neurological injury [6][7][8][9] and TBI [10]. When a pan-caspases inhibitor, Z-VAD-FMK, was used to block ''extrinsic'' apoptosis, tumor necrosis factor-a (TNF-a)-induced necroptotic cell death which showed a necrotic morphologic feature could serve as a backup mechanism of cellular demise [11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Necrostatin-1 Suppresses Autophagy and Apoptosis in Mice Traumatic Brain Injury Model

et al. 2012

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Traumatic brain injury (TBI) results in neuronal apoptosis, autophagic cell death and necroptosis. Necroptosis is a newly discovered caspases-independent programmed necrosis pathway which can be triggered by activation of death receptor. Previous works identified that necrostatin-1 (NEC-1), a specific necroptosis inhibitor, could reduce tissue damage and functional impairment through inhibiting of necroptosis process following TBI. However, the role of NEC-1 on apoptosis and autophagy after TBI is still not very clear. In this study, the amount of TBI-induced neural cell deaths were counted by PI labeling method as previously described. The expression of autophagic pathway associated proteins (Beclin-1, LC3-II, and P62) and apoptotic pathway associated proteins (Bcl-2 and caspase-3) were also respectively assessed by immunoblotting. The data showed that mice pretreated with NEC-1 reduced the amount of PI-positive cells from 12 to 48 h after TBI. Immunoblotting results showed that NEC-1 suppressed TBI-induced Beclin-1 and LC3-II activation which maintained p62 at high level. NEC-1 pretreatment also reversed TBI-induced Bcl-2 expression and caspase-3 activation, as well as the ratio of Beclin-1/Bcl-2. Both 3-MA and NEC-1 suppressed TBI-induced caspase-3 activation and LC3-II formation, Z-VAD only inhibited caspase-3 activation but increased LC3-II expression at 24 h post-TBI. All these results revealed that multiple cell death pathways participated in the development of TBI, and NEC-1 inhibited apoptosis and autophagy simultaneously. These coactions may further explain how can NEC-1 reduce TBI-induced tissue damage and functional deficits and reflect the interrelationship among necrosis, apoptosis and autophagy.

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“…The loss of glucose and oxygen is the primary insult of ischemia to brain cells, and the subsequent intracellular events, such as depletion of ATP, acidification, and generation of reactive oxygen species, make brain cells susceptible to ischemic damage [19]. This ischemic stress can be mimicked by OGD in vitro.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes

et al. 2015

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In cerebral ischemia, studies of cell death have focused primarily on neurons, but recent work indicates that ischemia also causes damage to astrocytes. Activation of astrocytes is a typical brain response to stress stimuli and is evidenced by changes in cellular function and morphology, as well as upregulation of glial fibrillary acidic protein. The tumor-suppressor transcription factor p53 has recently been implicated as a mediator of ischemia-induced neuronal death, but very little is known about its role in the activation or the death of astrocytes. The present study investigated the role of p53 in astrocyte and neuronal toxicity using in-vitro and in-vivo ischemic stroke models. We showed that p53 is activated in ischemic brains and in oxygen-glucose deprivation (OGD)-induced cell death in neurons and astrocytes. Inhibition of p53 activity using either pifithrin-α or small interference RNA interference reduced OGD-induced cell death and pifithrin-α reversed OGD-induced impairment of glutamate uptake in astrocytes, suggesting that p53 might play a key role in mediating neurotoxicity and gliotoxicity in ischemic brain injury. This study shows that p53 is activated in astrocytes during ischemia and that inhibition of the activity of this molecule prevents not only OGD-induced neuronal and astrocytic death but also astrocyte activation and impaired glutamate uptake. These findings suggest that p53 may be a valuable therapeutic target in ischemic brain injury.

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Characterisation of neuronal cell death in acute and delayed in vitro ischemia (oxygen–glucose deprivation) models

Cited by 55 publications

References 23 publications

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Necrostatin-1 Suppresses Autophagy and Apoptosis in Mice Traumatic Brain Injury Model

Inhibition of p53 attenuates ischemic stress-induced activation of astrocytes

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