A Dual Role of the NF-κB Pathway in Neonatal Hypoxic-Ischemic Brain Damage

Nijboer, Cora H.; Heijnen, Cobi J.; Groenendaal, Floris; May, Michael J.; Bel, Frank van; Kavelaars, Annemieke

doi:10.1161/strokeaha.108.516401

Cited by 99 publications

(99 citation statements)

References 24 publications

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“…Therefore, it is unclear to what extent proinflammatory cytokines contributed to the increased LPS-induced brain vulnerability in the present study. Others have found that inhibition of NF-B activity attenuates HI brain injury in neonatal mice, independent of cytokine production (41,42). In this study, we found an increased basal level of NF-B activation, as indicated by p-IB, but diminished NF-B activation in MyD88 KO mice in response to LPS.…”

Section: Discussionsupporting

confidence: 61%

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

Wang

Stridh

et al. 2009

The Journal of Immunology

153

143

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Neurological deficits in children, including cerebral palsy, are associated with prior infection during the perinatal period. Experimentally, we have shown that pre-exposure to the Gram-negative component LPS potentiates hypoxic-ischemic (HI) brain injury in newborn animals. LPS effects are mediated by binding to TLR4, which requires recruitment of the MyD88 adaptor protein or Toll/IL-1R domain-containing adapter inducing IFN-β for signal transduction. In this study, we investigated the role of MyD88 in neonatal brain injury. MyD88 knockout (MyD88 KO) and wild-type mice were subjected to left carotid artery ligation and 10% O2 for 50 min on postnatal day 9. LPS or saline were administered i.p. at 14 h before HI. At 5 days after HI in wild-type mice, LPS in combination with HI caused a significant increase in gray and white matter tissue loss compared with the saline-HI group. By contrast, in the MyD88 KO mice there was no potentiation of brain injury with LPS-HI. MyD88 KO mice exhibited reduced NFκB activation and proinflammatory cytokine-chemokine expression in response to LPS. The number of microglia and caspase-3 activation was increased in the brain of MyD88 KO mice after LPS exposure. Collectively, these findings indicate that MyD88 plays an essential role in LPS-sensitized HI neonatal brain injury, which involves both inflammatory and caspase-dependent pathways.

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Section: Discussionsupporting

confidence: 61%

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

Wang

Stridh

et al. 2009

The Journal of Immunology

153

143

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“…As FLIP is under the transcriptional control of NFkB, the effects on FLIP gene and protein expression in necrostatin-treated mice serve as a reporter of decreased NFkB activity in these mice, whether decreased NFkB is a direct or indirect result of necrostatin treatment. Early inhibition of NFkB is neuroprotective in this model (Nijboer et al, 2008). We find that HI induced a three-fold increase in NFkB activity in vehicle-treated mice, which is not seen in necrostatin-treated mice.…”

Section: Discussionmentioning

confidence: 52%

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

Northington

Chavez‐Valdez

Graham

et al. 2010

J Cereb Blood Flow Metab

188

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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“…5,6 JBD is the JNK binding domain of JNK-interacting protein-1 and acts as a specific JNK inhibitor. 7 The TNF-␣ inhibitor etanercept (5 mg/kg; Wyeth Pharmaceuticals Inc, Philadelphia, Pa) was administered intraperitoneally directly after HI.…”

Section: Animalsmentioning

confidence: 99%

“…3,4 In previous studies, we investigated the contribution of NF-B to HI brain injury in neonatal postnatal Day 7 rat pups by administration of TAT-NBD, an established NF-B inhibitor that rapidly distributed to the brain after intraperitoneal treatment. 5,6 NF-B inhibition by TAT-NBD markedly reduced brain injury as determined at 48 hours or at 6 weeks after the insult. 5 TAT-NBD treatment attenuated upregulation and mitochondrial association of the NF-B target p53 and increased upregulation of antiapoptotic Bcl family members.…”

mentioning

confidence: 95%

“…5 TAT-NBD treatment attenuated upregulation and mitochondrial association of the NF-B target p53 and increased upregulation of antiapoptotic Bcl family members. 5,6 Remarkably, however, HI-induced pro-and anti-inflammatory cytokine production was not affected by NF-B inhibition. 5 We address the question how HI-induced cerebral cytokine production is regulated when NF-B is inhibited.…”

mentioning

confidence: 95%

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Alternate Pathways Preserve Tumor Necrosis Factor-α Production After Nuclear Factor-κB Inhibition in Neonatal Cerebral Hypoxia–Ischemia

Nijboer

Heijnen

Groenendaal

et al. 2009

Stroke

Self Cite

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Background and Purpose-Nuclear factor-B (NF-B) is an important regulator of inflammation and apoptosis. We showed previously that NF-B inhibition by intraperitoneal TAT-NBD treatment strongly reduced neonatal hypoxicischemic (HI) brain damage. Neuroprotection by TAT-NBD was not associated with inhibition of cerebral cytokine production. We investigated how tumor necrosis factor-␣ (TNF-␣) production is maintained after NF-B inhibition and whether TNF-␣ contributes to brain damage. Methods-Postnatal Day 7 rats were subjected to unilateral carotid artery occlusion and hypoxia. Rats were treated immediately after HI with TAT-NBD, the JNK inhibitor TAT-JBD, and/or the TNF-␣ inhibitor etanercept. We determined brain damage, NF-B and AP-1 activity, Gadd45␤, XIAP, (P-)TAK1, TNF-␣, and TNF receptor expression. Results-Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNF-␣ production. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45␤, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-B and JNK/AP-1 abrogated HI-induced TNF-␣ production. However, this treatment reduced the neuroprotective effect of NF-B inhibition alone. We show that etanercept was detectable in the HI brain after intraperitoneal administration and that etanercept treatment also reduced the neuroprotective effect of NF-B inhibition. Finally, NF-B inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression. Conclusions-When

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A Dual Role of the NF-κB Pathway in Neonatal Hypoxic-Ischemic Brain Damage

Cited by 99 publications

References 24 publications

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner

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

Alternate Pathways Preserve Tumor Necrosis Factor-α Production After Nuclear Factor-κB Inhibition in Neonatal Cerebral Hypoxia–Ischemia

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