Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

Northington, Frances J.; Chavez‐Valdez, Raul; Graham, Ernest M.; Razdan, Sheila; Gauda, Estelle B.; Martin, Lee J.

doi:10.1038/jcbfm.2010.72

Cited by 192 publications

(208 citation statements)

References 41 publications

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“…A recent study found that Nmnat1 mediates its axonal protective effect in the presence of activated caspase-6 after tropic factor deprivation in dorsal root ganglion neurons (18). Interestingly, necrostatin, a small-molecule inhibitor of programmed necrosis (necroptosis), also fails to inhibit the activation of the caspase-3 pathways in animal models of neonatal brain injury (47) even though it provides significant protection in neonatal H-I and other mice models of acute injury (47)(48)(49). Whether the pathways activated by Nmnat1 and necrostatin overlap is unclear and will be an important area for future study.…”

Section: Discussionmentioning

confidence: 99%

“…Model of neuronal cell death in neonatal H-I initiated by NMDAmediated excitotoxicity. Excitotoxicity after neonatal H-I initiates necrosis and apoptosis as well as cell death that has features of both necrosis and apoptosis (3,10,21,46,47). Pan-caspase and caspase-3-specific inhibitors as well as overexpression of Bcl-XL and knockout of Bax significantly protect against neonatal H-I in rats and mice by blocking caspase-dependent celldeath pathways (6,23,41,42).…”

Section: Discussionmentioning

confidence: 99%

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Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…At least for the kidney, it appears that necroptosis predominates over apoptosis and similar suggestions have been made in myocardial IRI (11,25). However, existing data that imply protection by interference with necroptosis in various in vivo models used the RIPK1 kinase inhibitor necrostatin (Nec)-1 to inhibit necrotic signaling (10,11,26,27). However, Nec-1 has recently been discussed to directly influence the immune system, besides its effects to block release of CDAMPs (28,29).…”

mentioning

confidence: 82%

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Linkermann

Bräsen

Darding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

503

456

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Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptorinteracting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia-reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.RIP3 | RIP1 | programmed necrosis | apoptosis

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“…Experiments using a specific necroptotic inhibitor, necrostatin-1 (Nec-1), and one of its derivatives, 7-chloroindolenecrostatin-1 (7-Cl-Nec-1), have confirmed that necroptosis is involved in the ischemic brain injury induced by focal cerebral ischemia and neonatal HI [14,77] . The protection effect of 7-Cl-Nec-1 is readily detectable, even when the compound is administered 6 h after the onset of cerebral ischemic injury [14] , at which point the administration of zVAD-fmk no longer decreases infarct volume [78] , indicating that necroptosis may participate in ischemia-induced delayed cell death.…”

Section: Autophagy Is a Response To Necroptotic Cell Deathmentioning

confidence: 99%

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

Zhang

2011

Acta Pharmacol Sin

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Autophagy is a highly regulated cellular mechanism that leads to degradation of long-lived proteins and dysfunctional organelles. The process has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. Recent studies show the existence of autophagy in cerebral ischemia, but no consensus has yet been reached regarding the functions of autophagy in this condition. This article highlights the activation of autophagy during cerebral ischemia and/or reperfusion, especially in neurons and astrocytes, as well as the role of autophagy in neuronal or astrocytic cell death and survival. We propose that physiological levels of autophagy, presumably caused by mild to modest hypoxia or ischemia, appear to be protective. However, high levels of autophagy caused by severe hypoxia or ischemia and/or reperfusion may cause self-digestion and eventual neuronal and astrocytic cell death. We also discuss that oxidative and endoplasmic reticulum (ER) stresses in cerebral hypoxia or ischemia and/or reperfusion are potent stimuli of autophagy in neurons and astrocytes. In addition, we review the evidence suggesting a considerable overlap between autophagy on one hand, and apoptosis, necrosis and necroptosis on the other hand, in determining the outcomes and final morphology of damaged neurons and astrocytes.

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Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

Cited by 192 publications

References 41 publications

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

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