Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia

Research output: Contribution to journalArticle

Abstract

Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if Nec-1 treatment following neonatal HI attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1. μL (80. μmol) of Nec-1 or vehicle. Nec-1 treatment prevented nitric oxide (NO•), inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine increase, and attenuated glutathione oxidation that was found in vehicle-treated mice at 3. h following HI. Similarly, Nec-1 following HI prevented: (i) up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and BCL2/adenovirus E1B 19. kDa protein-interacting protein 3 (BNIP3) expression, (ii) decline in mitochondrial complex-I activity, (iii) decrease in ATP levels, and (iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)192-203
Number of pages12
JournalNeuroscience
Volume219
DOIs
StatePublished - Sep 6 2012

Fingerprint

Astrocytes
Ischemia
Neurons
Receptor-Interacting Protein Serine-Threonine Kinases
Protein Kinases
Glutathione
Nitric Oxide
Up-Regulation
Hypoxia-Inducible Factor 1
necrostatin-1
Hypoxia
Glial Fibrillary Acidic Protein
Wounds and Injuries
Nitric Oxide Synthase Type II
Prosencephalon
Secondary Prevention
Adenoviridae
Signal Transduction
Proteins
Oxidative Stress

Keywords

  • Astrocytes
  • Hypoxia-ischemia
  • Mitochondria
  • Neurons
  • Receptor interacting protein-1 kinase
  • Regulated necrosis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{bddac37fa76d43a6bccb631f12ee83d6,
title = "Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia",
abstract = "Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if Nec-1 treatment following neonatal HI attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1. μL (80. μmol) of Nec-1 or vehicle. Nec-1 treatment prevented nitric oxide (NO•), inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine increase, and attenuated glutathione oxidation that was found in vehicle-treated mice at 3. h following HI. Similarly, Nec-1 following HI prevented: (i) up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and BCL2/adenovirus E1B 19. kDa protein-interacting protein 3 (BNIP3) expression, (ii) decline in mitochondrial complex-I activity, (iii) decrease in ATP levels, and (iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.",
keywords = "Astrocytes, Hypoxia-ischemia, Mitochondria, Neurons, Receptor interacting protein-1 kinase, Regulated necrosis",
author = "Raul Chavez-Valdez and Martin, {Lee J} and Flock, {D. L.} and Frances Northington",
year = "2012",
month = "9",
day = "6",
doi = "10.1016/j.neuroscience.2012.05.002",
language = "English (US)",
volume = "219",
pages = "192--203",
journal = "Neuroscience",
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TY - JOUR

T1 - Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia

AU - Chavez-Valdez, Raul

AU - Martin, Lee J

AU - Flock, D. L.

AU - Northington, Frances

PY - 2012/9/6

Y1 - 2012/9/6

N2 - Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if Nec-1 treatment following neonatal HI attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1. μL (80. μmol) of Nec-1 or vehicle. Nec-1 treatment prevented nitric oxide (NO•), inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine increase, and attenuated glutathione oxidation that was found in vehicle-treated mice at 3. h following HI. Similarly, Nec-1 following HI prevented: (i) up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and BCL2/adenovirus E1B 19. kDa protein-interacting protein 3 (BNIP3) expression, (ii) decline in mitochondrial complex-I activity, (iii) decrease in ATP levels, and (iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.

AB - Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if Nec-1 treatment following neonatal HI attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1. μL (80. μmol) of Nec-1 or vehicle. Nec-1 treatment prevented nitric oxide (NO•), inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine increase, and attenuated glutathione oxidation that was found in vehicle-treated mice at 3. h following HI. Similarly, Nec-1 following HI prevented: (i) up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and BCL2/adenovirus E1B 19. kDa protein-interacting protein 3 (BNIP3) expression, (ii) decline in mitochondrial complex-I activity, (iii) decrease in ATP levels, and (iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.

KW - Astrocytes

KW - Hypoxia-ischemia

KW - Mitochondria

KW - Neurons

KW - Receptor interacting protein-1 kinase

KW - Regulated necrosis

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U2 - 10.1016/j.neuroscience.2012.05.002

DO - 10.1016/j.neuroscience.2012.05.002

M3 - Article

C2 - 22579794

AN - SCOPUS:84864003121

VL - 219

SP - 192

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JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

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