NF-κB signaling in cerebral ischemia

Ridder, Dirk A.; Schwaninger, Markus

doi:10.1016/j.neuroscience.2008.07.007

Cited by 345 publications

(277 citation statements)

References 112 publications

(157 reference statements)

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“…Based on these findings, probucol exerts anti-inflammatory properties via the inhibition of pro-inflammatory cytokines. NF-κB is activated in cerebral ischemia and promotes ischemic brain injury through the regulation of the expression of various genes that are involved in the production of many pro-inflammatory cytokines and enzymes that are related to the inflammatory process [41,42] . The phosphorylation of NF-κB p65 (Ser536) is required for the activation and nuclear translocation of NF-κB, which results in transcriptional induction of inflammation-associated genes [42] .…”

Section: Discussionmentioning

confidence: 99%

“…NF-κB is activated in cerebral ischemia and promotes ischemic brain injury through the regulation of the expression of various genes that are involved in the production of many pro-inflammatory cytokines and enzymes that are related to the inflammatory process [41,42] . The phosphorylation of NF-κB p65 (Ser536) is required for the activation and nuclear translocation of NF-κB, which results in transcriptional induction of inflammation-associated genes [42] . We demonstrated that probucol prevents LPS-induced NF-κB activity and nuclear translocation (Figure 3), which suggests that the attenuation of the NF-κB signaling pathways in microglia by probucol might result in the down-regulation of inflammatory mediators and cytokines and thus result in an anti-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

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Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

et al. 2016

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Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg -1 ·d -1 , po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, preadministration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total-and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

et al. 2016

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“…In line with this concept, deletion of the NF-kB subunits p50 or p65 reduced the infarct size in a mouse model of stroke. 3,8,9 Furthermore, inhibition or deletion of the upstream kinase IKK protected against acute neurodegeneration in cerebral ischemia. 6 In Parkinson's and Huntington's disease,a detrimental effect of IKK has been reported.…”

mentioning

confidence: 98%

“…3,4 Although the mechanism of NF-kB activation in cerebral ischemia is still not completely understood, there is evidence that the upstream kinase IKK is involved. [5][6][7] NF-kB is well known for its anti-apoptotic action.…”

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confidence: 99%

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

et al. 2011

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Neuronal apoptosis contributes to ischemic brain damage and neurodegenerative disorders. Key regulators of neuronal apoptosis are the transcription factor NF-jB and the MAP kinases p38/MAPK and JNK, which share a common upstream activator, the mitogen-activated protein kinase kinase kinase (MAP3K) TGFb-activated kinase 1 (TAK1). Here we investigate the function of TAK1 in ischemia-induced neuronal apoptosis. In primary cortical neurons, TAK1 was activated by oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia. We found that short-term inhibition of TAK1 protected against OGD in vitro and reduced the infarct volume after middle cerebral artery occlusion in vivo. Prolonged inhibition or deletion of the TAK1 gene in neurons was, however, not protective. Short-term, but not prolonged inhibition of TAK1 interfered with the activation of p38/MAPK and JNK by OGD, the induction of the pro-oxidative genes Cox-2, Nox-2, and p40 phox , and the formation of superoxide. We found that prolonged TAK1 inhibition upregulated another MAP3K, apoptosis signal-regulating kinase-1, which is able to compensate for TAK1 inhibition. Our study demonstrates that TAK1 is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia.

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“…Результатом активации тирозинкиназы В явля-ется фосфорилирование транскрипционного фактора κВ (NFκВ) и его транслокация в ядро клетки. Как известно, NFκВ стимулирует экспрессию ряда цитопротективных белков, участвующих в формировании поздней ишемиче-ской толерантности ГМ [9].…”

Section: механизмы ослабления феномена эксайтотоксичности при ишемичеunclassified

Molecular Mechanisms of Development of Cerebral Tolerance to Ischemia (Review. Part 2)

Шляхто¹,

Баранцевич²,

Shcherbak³

et al. 2012

Annals RAMS

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Антиапоптотическое действие прекондиционированияИшемия и в особенности реперфузия запускают процесс программируемой гибели нейронов -апоптоз, механизмы которого на сегодняшний день достаточно хорошо изучены. При прекондиционировании головного мозга (ПреК ГМ) запускаются многочисленные процессы, препятствующие апоптозу, которые могут быть связаны с активацией рецепторов, внутриклеточных киназных каскадов, транскрипционных факторов, определенных митохондриальных белков и ядерных эффекторов. Более подробная характеристика молекулярных механизмов, участвующих как в запуске апоптоза, так и в его предот-вращении в процессе наступления ишемической толе-рантности, представлена в табл. 1. Известно, в частности, что индуцируемый ПреК транскрипционный фактор -цАМФ-зависимый связывающий белок (CREB) -способствует увеличению интенсивности синтеза анти-апоптотических белков BCL2 и BCLX L . Кроме того, под действием ПреК происходит стабилизация митохондри-ального мембранного потенциала, снижается высвобож-дение митохондриального цитохрома С, а также умень-шается интенсивность синтеза каспазы 3 и снижается активность ядерного белка p53 [1]. На модели четырех-сосудистой ишемии ГМ у крыс было показано, что меха-низмы предотвращения апоптоза нейронов СА1-зоны гиппокампа под действием ишемического ПреК вклю-чают активацию фосфатидилинозитол-3ОН-киназы (PI3K) и протеинкиназы В с последующей блокировкой сигнальных путей апоптоза [2]. В частности, ишемиче-ское ПреК предотвращало транслокацию в митохон-дрии проапоптотического фактора BAD, его связывание с BCL-X L и расщепление последнего с образованием проа-поптотического фрагмента ∆N-Bcl-X L . Помимо этого,

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NF-κB signaling in cerebral ischemia

Cited by 345 publications

References 112 publications

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Molecular Mechanisms of Development of Cerebral Tolerance to Ischemia (Review. Part 2)

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