Necrostatin-1 Reduces Neurovascular Injury after Intracerebral Hemorrhage

King, M.E.; Whitaker-Lea, Wittstatt Alexandra; Campbell, James M.; Alleyne, Cargill H.; Dhandapani, Krishnan M.

doi:10.1155/2014/495817

Cited by 55 publications

(39 citation statements)

References 74 publications

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“…Suppression of necroptosis plays an important role in normal tissue development and homoeostasis [42]. Nec-1 is an inhibitor of RIPK1 which inhibits necroptosis and thereby promotes cell survival [43]. In the present study, we demonstrate a role for sphingolipids in nutrient and energy-deprivation-induced necroptosis.…”

Section: Discussionsupporting

confidence: 59%

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Sundaram

Mather

Marimuthu

et al. 2016

Biochemical Journal

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Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase−/−) were protected from 2DG/AA. Although nCDase−/− cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase−/− cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase−/− MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient-deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

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Section: Discussionsupporting

confidence: 59%

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Sundaram

Mather

Marimuthu

et al. 2016

Biochemical Journal

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“…Nec-1 mediates neuroprotective effects in rodent models of acute and chronic neurological conditions, including adult stroke (146), neonatal hypoxia/ischemia (H/I) (147, 148), retinal ischemia (149), retinal detachment (150–152), subarachnoid hemorrhage (153, 154), traumatic brain injury (155), spinal cord injury (156–159), and amyotrophic lateral sclerosis (160). The ability of Nec-1 to counteract manifestations of amyotrophic lateral sclerosis in mice was backed up by the knockdown of RIPK1 as well as by data obtained using human cells treated with necrosulfonamide (NSA, a chemical that inhibits human MLKL) (160).…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

536

398

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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.

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“…21,22,59 However, the recent discovery of a novel inflammatory cellular death pathway, necroptosis, has led to a series of studies investigating the role of this unique form of inflammatory cell death in ICH. 31,32,34,[60][61][62][63] Necroptosis is engaged by engagement of innate pattern recognition receptors that respond to both foreign pathogens as well as endogenous "danger signals" of tissue injury. Activation of these receptors results in formation of an intracellular "inflammasome" complex that activates caspase 1 as well as caspase 3, which promotes the release of inflammatory factors such as IL-1β and highmobility group box 1 (HMGB1), as well as initiation of a controlled cell death resembling, but distinct from, apoptosis.…”

Section: Production Of Inflammatory Factorsmentioning

confidence: 99%

Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage

Askenase

Sansing

2016

Semin Neurol

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Intracerebral hemorrhage (ICH) is a major health concern, with high rates of mortality and morbidity and no highly effective clinical interventions. Basic research in animal models of ICH has provided insight into its complex pathology, in particular revealing the role of inflammation in driving neuronal death and neurologic deficits after hemorrhage. The response to ICH occurs in four distinct phases: (1) initial tissue damage and local activation of inflammatory factors, (2) inflammation-driven breakdown of the blood–brain barrier, (3) recruitment of circulating inflammatory cells and subsequent secondary immunopathology, and (4) engagement of tissue repair responses that promote tissue repair and restoration of neurologic function. The development of CNS inflammation occurs over many days after initial hemorrhage and thus may represent an ideal target for treatment of the disease, but further research is required to identify the mechanisms that promote engagement of inflammatory versus anti-inflammatory pathways. In this review, the authors examine how experimental models of ICH have uncovered critical mediators of pathology in each of the four stages of the inflammatory response, and focus on the role of the immune system in these processes.

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Necrostatin-1 Reduces Neurovascular Injury after Intracerebral Hemorrhage

Cited by 55 publications

References 74 publications

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death

Necroptosis: Mechanisms and Relevance to Disease

Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage

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