Hypoxia Ischemia-Mediated Cell Death in Neonatal Rat Brain

Gill, Martin B.; Perez‐Polo, J. Regino

doi:10.1007/s11064-008-9649-1

Cited by 54 publications

(51 citation statements)

References 124 publications

(175 reference statements)

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“…Due to the variation in the Atg7 suppression achieved between different transfection experiments using siRNA (see text), similar data obtained from three replicate experiments were not combined for quantification here. Asterisks indicate time points where there was a significant difference between nRNA and siAtg7 populations (*P \ 0.001, **P \ 0.01, ***P \ 0.001) Caspase-independent cell death following H 2 O 2 insult requires autophagic machinery in C57/Black 6 J cortical neurons Acute oxidative stress, such as that following ischemic reperfusion injury during stroke can invoke a necrotic-like cell death that is devoid of caspase activity at the core or center of infarction [23,24,42]. We have previously shown that following acute H 2 O 2 insult, cortical neurons from C57 Black/6 J mice undergo programmed necrosis (PCDtype III) that is independent of effector caspase activity (specifically caspase-3 and caspase-7) [26].…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis has previously been defined as a programmed or regulated type of cell death, characterized by the activation of caspases, while necrosis has been thought of as a caspase-independent, unregulated process. However, contemporary evidence supports the thesis that neuronal PCD is not exclusively apoptotic; rather it is a multifaceted phenomenon that encompasses autophagy and programmed necrosis, with extensive crosstalk between the three death pathways [22][23][24]. Within a given population of neurons, it is thought that multiple PCD pathways can be invoked concurrently in response to a single injury or insult [25].…”

Section: Introductionmentioning

confidence: 99%

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Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death

Higgins

Devenish

Beart

et al. 2011

Cell. Mol. Life Sci.

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Primary neurons undergo insult-dependent programmed cell death. We examined autophagy as a process contributing to cell death in cortical neurons after treatment with either hydrogen peroxide (H(2)O(2)) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment, neither was observed following H(2)O(2) treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H(2)O(2), but slowly with staurosporine, as quantified by processing of endogenous LC3. Autophagic induction by both stressors increased the abundance of fluorescent puncta formed by GFP-LC3, which could be blocked by 3-methyladenine. Significantly, such inhibition of autophagy blocked cell death induced by H(2)O(2) but not staurosporine. Suppression of Atg7 inhibited cell death by H(2)O(2), but not staurosporine, whereas suppression of Beclin 1 prevented cell death by both treatments, suggesting it has a complex role regulating both apoptosis and autophagy. We conclude that autophagic mechanisms are activated in an insult-dependent manner and that H(2)O(2) induces autophagic cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death

Higgins

Devenish

Beart

et al. 2011

Cell. Mol. Life Sci.

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“…4 Other physiological or pharmacological effects such as heat, hypoxia, ischemia, disease, glucose and metabolic starvation, and changes in lipid metabolism are also potent inducers of the ER stress pathway. 35 ER stress has been implicated in a number of diseases including ischemia/reperfusion of the brain and heart, 35,68 heart failure, 35 and diabetes, 69 with the UPR activated in cardiac tissues by decreases in ATP, ER Ca 2ϩ , or UDPglucose. 70 In the heart, hypoxia, ischemia/reperfusion, hypertrophy, pressure overload, and drug-induced insults can result in activation of ER stress.…”

Section: Er Stress In the Heartmentioning

confidence: 99%

Biology of Endoplasmic Reticulum Stress in the Heart

Groenendyk

Sreenivasaiah

Kim

et al. 2010

Circulation Research

283

231

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Abstract:The endoplasmic reticulum (ER) is a multifunctional intracellular organelle supporting many processes required by virtually every mammalian cell, including cardiomyocytes. It performs diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N-linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca 2؉ homeostasis. Perturbation of ER-associated functions results in ER stress via the activation of complex cytoplasmic and nuclear signaling pathways, collectively termed the unfolded protein response (UPR) (also known as misfolded protein response), leading to upregulation of expression of ER resident chaperones, inhibition of protein synthesis and activation of protein degradation. The UPR has been associated with numerous human pathologies, and it may play an important role in the pathophysiology of the heart. ER stress responses, ER Ca 2؉ buffering, and protein and lipid turnover impact many cardiac functions, including energy metabolism, cardiogenesis, ischemic/reperfusion, cardiomyopathies, and heart failure. ER proteins and ER stress-associated pathways may play a role in the development of novel UPR-targeted therapies for cardiovascular diseases. (Circ Res. 2010;107:1185-1197.) Key Words: endoplasmic reticulum stress Ⅲ misfolded protein response Ⅲ autophagy Ⅲ endoplasmic reticulum-associated degradation Ⅲ cardiac disease T he endoplasmic reticulum (ER) is a centrally located, multifunctional, and multiprocess intracellular organelle supporting many mechanisms required by virtually every mammalian cell, including cardiomyocytes. The membrane performs a remarkable number of diverse functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N-linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca 2ϩ homeostasis. 1 Development and maintenance of optimally functioning ER membrane is essential for virtually all cellular activities, from intracellular signaling to control of transcriptional pathways; ion fluxes to control of energy metabolism; protein synthesis to multisubunit assembly; and lipid synthesis to transcriptional regulation of steroid metabolism. One of the major advantages of the centrally located ER network for the cell is the ability to control the composition and the dynamics of the ER luminal environment in an extracellular environmentindependent way. Furthermore, the ER is not an isolated organelle because it has developed sophisticated mechanisms of communication with many other cellular compartments,

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“…comes are multifaceted within a holistic framework of interplay between multiple injury mechanisms, often operating in parallel [43][44][45] (Fig. 1).…”

Section: Mitochondrial Respiratory Complexes Oxidative Damage and Pcdmentioning

confidence: 99%

Oxidative Stress: Emerging Mitochondrial and Cellular Themes and Variations in Neuronal Injury

Higgins

Beart

Shin

et al. 2010

JAD

134

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Abstract. Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer's disease, and other pathologies including Parkinson's disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances.

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Hypoxia Ischemia-Mediated Cell Death in Neonatal Rat Brain

Cited by 54 publications

References 124 publications

Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death

Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death

Biology of Endoplasmic Reticulum Stress in the Heart

Oxidative Stress: Emerging Mitochondrial and Cellular Themes and Variations in Neuronal Injury

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