Necrostatin-1 Reduces Histopathology and Improves Functional Outcome after Controlled Cortical Impact in Mice

You, Zerong; Savitz, Sean I; Yang, Jinsheng; Degterev, Alexei; Yuan, Junying; Cuny, Gregory D.; Moskowitz, Michael A.; Whalen, Michael J.

doi:10.1038/jcbfm.2008.44

Cited by 247 publications

(229 citation statements)

References 32 publications

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“…This is the first study to show the neuroprotective efficacy of necrostatin in any model of neonatal brain injury. Previous studies have shown that necrostatin is neuroprotective in adult mouse stroke and traumatic brain injury models as shown by histologic and behavioral outcomes (Degterev et al, 2005;You et al, 2008). Protection in necrostatin-treated neonatal mice is demonstrable in the ipsilateral forebrain and thalamus at 4 days (P11) and persists at 21 days (P28) after HI.…”

Section: Discussionmentioning

confidence: 98%

“…Necrostatin protects by inhibiting RIP1 kinase activation with possible downstream antiinflammatory effects (You et al, 2008) and perhaps other mechanisms. Although necrostatin has no intrinsic antioxidant activity, it blocks tumor necrosis factor (TNF)-induced activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Kim et al, 2007) and nitric oxide-mediated necrosis (Davis et al, 2010) by the inhibition of both Nox1 and mitochondrialderived oxygen-free radicals.…”

Section: Introductionmentioning

confidence: 99%

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

Northington

Chavez‐Valdez

Graham

et al. 2010

J Cereb Blood Flow Metab

192

194

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Necrostatin-1 inhibits receptor-interacting protein (RIP)-1 kinase and programmed necrosis and is neuroprotective in adult rodent models. Owing to the prominence of necrosis and continuum cell death in neonatal hypoxia-ischemia (HI), we tested whether necrostatin was neuroprotective in the developing brain. Postnatal day (P)7 mice were exposed to HI and injected intracerebroventricularly with 0.1 lL of 80 lmol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, or vehicle. Necrostatin significantly decreased injury in the forebrain and thalamus at P11 and P28. There was specific neuroprotection in necrostatin-treated males. Necrostatin treatment decreased necrotic cell death and increased apoptotic cell death. Hypoxia-ischemia enforced RIP1-RIP3 complex formation and inhibited RIP3-FADD (Fas-associated protein with death domain) interaction, and these effects were blocked by necrostatin. Necrostatin also decreased HI-induced oxidative damage to proteins and attenuated markers of inflammation coincidental with decreased nuclear factor-jB and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1b-converting enzyme)-inhibitory protein) gene and protein expression. In this model of severe neonatal brain injury, we find that cellular necrosis can be managed therapeutically by a single dose of necrostatin, administered after HI, possibly by interrupting RIP1-RIP3-driven oxidative injury and inflammation. The effects of necrostatin treatment after HI reflect the importance of necrosis in the delayed phases of neonatal brain injury and represent a new direction for therapy of neonatal HI.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Northington

Chavez‐Valdez

Graham

et al. 2010

J Cereb Blood Flow Metab

192

194

View full text Add to dashboard Cite

show abstract

“…No differences in visible platform performance were noted among CHI groups (P ¼ 0.71 for group) and no differences in hidden, visible platform, or probe trials were noted between CHI-VEH and CHI-Akt viii groups. mTOR and Akt in concussive brain injury X Zhu et al after CCI; 17,18 however, Nec-1 has not been reported in a non-cell death TBI model. The current study suggests a possible link between the beneficial effects of Nec-1 on cognitive function and augmentation of Akt/mTOR signaling after CHI, a finding that lends support to the possibility that Akt/mTOR signaling is a protective response to CHI.…”

Section: Discussionmentioning

confidence: 99%

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

Zhu

Park

Golinski

et al. 2014

J Cereb Blood Flow Metab

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Akt (protein kinase B) and mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of cell death and cognitive outcome after cerebral contusion in mice; however, a role for Akt/mTOR in concussive brain injury has not been well characterized. In a mouse closed head injury (CHI) concussion traumatic brain injury (TBI) model, phosphorylation of Akt (p-Akt), mTOR (p-mTOR), and S6RP (p-S6RP) was increased by 24 hours in cortical and hippocampal brain homogenates (Po0.05 versus sham for each), and p-S6RP was robustly induced in IBA-1 þ microglia and glial fibrillary acidic protein-positive (GFAP þ ) astrocytes. Pretreatment with inhibitors of Akt or mTOR individually by the intracerebroventricular route reduced phosphorylation of their respective direct substrates FOXO1 (Po0.05) or S6RP (Po0.05) after CHI, confirming the activity of inhibitors. Rapamycin pretreatment significantly worsened hidden platform (Po0.01) and probe trial (Po0.05) performance in CHI mice. Intracerebroventricular administration of necrostatin-1 (Nec-1) before CHI increased hippocampal Akt and S6RP phosphorylation and improved place learning (probe trials, Po0.001 versus vehicle), whereas co-administration of rapamycin or Akt inhibitor with Nec-1 eliminated improved probe trial performance. These data suggest a beneficial role for Akt/mTOR signaling after concussion TBI independent of cell death that may contribute to improved outcome by Nec-1.

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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%

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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Necrostatin-1 Reduces Histopathology and Improves Functional Outcome after Controlled Cortical Impact in Mice

Cited by 247 publications

References 32 publications

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

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

Role of Akt and Mammalian Target of Rapamycin in Functional Outcome after Concussive Brain Injury in Mice

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

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