NF-kappaB signaling in cerebral ischemia.
The transcription factor NF-kappaB is a key regulator of hundreds of genes involved in cell survival and inflammation. There is ample evidence that NF-kappaB is activated in cerebral ischemia, mainly in neurons. Despite its well known role as an antiapoptotic factor, in cerebral ischemia NF-kappaB contributes to neuronal cell death, at least if the ischemia is severe enough to lead to irreversible brain damage. In contrast, NF-kappaB also seems to be responsible for the preconditioning effect of a transient and sublethal ischemia, perhaps by dampening its own subsequent full activation. Among the five NF-kappaB subunits, RelA and p50 are responsible for the detrimental effect in cerebral ischemia. Activation of NF-kappaB signaling is mediated by the upstream kinase inhibitor of kappaB kinase and is triggered by hypoxia, reactive oxygen species, and several inflammatory mediators. Interestingly, the complex NF-kappaB signaling pathway provides drug targets at several levels. Modulation of NF-kappaB signaling has the potential to interrupt multiple inflammatory and apoptotic mechanisms through one specific molecular target.
Ridder
D A
DA
Pharmacological Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Schwaninger
M
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002544:Cerebral Infarction / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019194:Ischemic Preconditioning; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA