Nuclear factor-κB activation in permanent intraluminal focal cerebral ischemia in the rat

Seegers, Hélène C.; Grillon, Emmanuelle; Trioullier, Yaël; Väth, Albert; Verna, Jean-Marc; Blum, David

doi:10.1016/s0304-3940(00)01245-3

Cited by 36 publications

(19 citation statements)

References 27 publications

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“…The absence of a significant ischemia-induced increase in NFκB activation is in contrast to findings from the majority of experimental global and focal brain ischemia studies [5,[7][8][9][10][11][12][13][14]. Our result is most likely accounted for by the inconsistent ischemic severity demonstrated in our model.…”

Section: Discussioncontrasting

confidence: 99%

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Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Nazarali

Paterson

2008

The Journal of Nutritional Biochemistry

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Protein-energy malnutrition (PEM) exacerbates functional impairment caused by brain ischemia. This is correlated with reactive gliosis, which suggests an increased inflammatory response. The objective of the current study was to investigate if PEM increases hippocampal activation of nuclear factor κB (NFκB), a transcription factor that amplifies the inflammatory response involved in ischemic brain injury. Mongolian gerbils (11-12 weeks old) were randomly assigned to control diet (12.5% protein) or protein-deficient diet (2%) for 4 weeks. The 2% protein group had a 15% decrease in voluntary food intake (P<.001; unpaired t test), resulting in PEM. Body weight after 4 weeks was 20% lower in the PEM group (P<.001). Gerbils were then exposed to sham surgery or global ischemia induced by 5-min bilateral common carotid artery occlusion. PEM independently increased hippocampal NFκB activation detected by electrophoretic mobility shift assay at 6 h after surgery (P=.014; 2-factor ANOVA). Ischemia did not significantly affect NFκB activation nor was there interaction between diet and ischemia. Serum glucose and cortisol concentrations at 6 h postischemia were unaltered by diet or ischemia. A second experiment using gerbils of the same age and feeding paradigm demonstrated that PEM also increases hippocampal NFκB activation in the absence of surgery. These findings suggest that PEM, which exists in 16% of elderly patients at admission for stroke, may worsen outcome by increasing activation of NFκB. Since PEM increased NFκB activation independent of ischemia or surgery, the data also have implications for the inflammatory response of the many individuals affected globally by PEM.

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Section: Discussioncontrasting

confidence: 99%

“…Nuclear factor κB (NFκB) is a transcription factor that is key in amplifying the inflammatory response involved in stroke pathophysiology [3,4]. Increased NFκB activation has been demonstrated in human stroke [5,6] and experimental models of brain ischemia [5,[7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Nazarali

Paterson

2008

The Journal of Nutritional Biochemistry

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“…Of note, the penumbra model differs from microglia stimulation by LPS, which activates both p38 MAPK and NF-B (Zhang and Stanimirovic, 2002;Kaushal et al, 2007); however, LPS, from Gram-negative bacteria, is clearly a poor model of ischemic stroke. More relevant is that p38 MAPK and NF-B activation have been observed in the penumbra in vivo after focal ischemia (Seegers et al, 2000;Krupinski et al, 2003), their inhibition is protective (Zhang and Stanimirovic, 2002), and both have been implicated in inflammation-induced neuron injury (Gabriel et al, 1999;Schneider et al, 1999;Sharp et al, 2000;Ferrer et al, 2003). Despite the likelihood of additional mechanisms in vivo, the present in vitro study supports targeting microglial group II metabotropic receptors, TNF-␣ overproduction, and NF-B for reducing inflammation-mediated neurotoxicity after ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Kaushal¹,

Schlichter²

2008

J. Neurosci.

289

225

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After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor B (NF-B), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-␣ (TNF-␣), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4Ј-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2ЈR,3ЈR)-2-(2Ј3Ј-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-␣ (not nitric oxide) and mediated TNF-␣-dependent neurotoxicity through activation of NF-B (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNF␣ overproduction, and NF-B activation to reduce neuron death in the ischemic penumbra.

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“…NF-kappa B, a transcription factor that is responsive to oxidative stress is upregulated in the penumbra, but declines in the centre of the ischemic lesion (Aronowski et al, 2000;Seegers et al, 2000). The prostaglandin synthesizing enzyme cyclo-oxygenase-2 (COX-2) is also strongly upregulated in the peri-infarct penumbra and can be detected in neutrophils, vascular cells and neurons Bidmon et al, 2000).…”

Section: Inflammationmentioning

confidence: 99%

Pathophysiology and Therapy of Experimental Stroke

2006

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1. Stroke is the neurological evidence of a critical reduction of cerebral blood flow in a circumscribed part of the brain, resulting from the sudden or gradually progressing obstruction of a large brain artery. Treatment of stroke requires the solid understanding of stroke pathophysiology and involves a broad range of hemodynamic and molecular interventions. This review summarizes research that has been carried out in many laboratories over a long period of time, but the main focus will be on own experimental research. 2. The first chapter deals with the hemodynamics of focal ischemia with particular emphasis on the collateral circulation of the brain, the regulation of blood flow and the microcirculation. In the second chapter the penumbra concept of ischemia is discussed, providing a detailed list of the physiological, biochemical and structural viability thresholds of ischemia and examples of how these thresholds can be applied for imaging the penumbra. The third chapter summarizes the pathophysiology of infarct progression, focusing on the role of peri-infarct depolarisation, the multitude of putative molecular injury pathways, brain edema and inflammation. Finally, the fourth chapter provides an overview of currently discussed therapeutic approaches, notably the effect of mechanical or thrombolytic reperfusion, arteriogenesis, pharmacological neuroprotection, ischemic preconditioning and regeneration. 3. The main emphasis of the review is placed on the balanced differentiation between hemodynamic and molecular factors contributing to the manifestation of ischemic injury in order to provide a rational basis for future therapeutic interventions.

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Nuclear factor-κB activation in permanent intraluminal focal cerebral ischemia in the rat

Cited by 36 publications

References 27 publications

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Pathophysiology and Therapy of Experimental Stroke

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