NF-kappaB signaling in cerebral ischemia.

Acute cerebral ischemia elicits an innate immune response that leads to a cascade of events that culminates in necrotic death of neurons and injury to their supportive structures in the neurovascular unit. Indeed, clinical studies have shown a close relationship between elevated levels of inflammatory markers and the risk for ischemic stroke. However, the signaling pathways that link these events are not well understood. A central regulator of inflammatory response is the transcription factor, nuclear factor-kappa B (NF-κB). The activation of NF-κB is required for the transcriptional induction of many proinflammatory mediators involved in innate immunity, such as cellular adhesion molecules, cytokines, and growth factors. Therefore, factors that modulate the activity of NF-κB could potentially regulate inflammatory processes in ischemic stroke. Here, we review the relationship between NF-κB and ischemic stroke, its role in the neurovascular unit, and discuss some animal models that suggest that this relationship is causal.

/pdf/nf-kb-and-innate-immunity-in-ischemic-stroke-578e9vsu0w.pdf

NF-κB and innate immunity in ischemic stroke.

Mitochondrial JNK phosphorylation as a novel therapeutic target to inhibit neuroinflammation and apoptosis after neonatal ischemic brain damage

Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used

Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

Neuroprotective agents for neonatal hypoxic-ischemic brain injury.

Activated nuclear factor-κB (NFκB) has been shown to increase transcription of several genes that could potentially contribute to neuronal damage, such as proinflammatory cytokines, chemokines, and inducible nitric oxide synthase. The aim of our study was to investigate whether inhibition of NFκB activation could prevent hypoxia/ischemia (HI)-induced cerebral damage in neonatal rats. We used a cell permeable peptide (NEMO binding domain [NBD] peptide) that is known to prevent the association of the regulatory protein NEMO with IKK, the kinase that activates NFκB. Via this mechanism, the NBD peptide can specifically block the activation of NFκB, without inhibiting basal NFκB activity. Cerebral HI was induced in neonatal rats by occlusion of the right carotid artery followed by 90 min of hypoxia (Fio2 = 0.08). Immediately upon reoxygenation, as well as 6 and 12 h later, rats were treated with vehicle or NBD peptide (20 mg/kg i.p.). Histologic analysis of brain damage was performed at 6 wk after HI. To assess NFκB activation, electromobility shift assays (EMSAs) were performed on brain nuclear extracts obtained 6 h after reoxygenation. Increased NFκB activity could be shown at 6 h after HI in both hemispheres. Peripheral administration of NBD peptide prevented this HI-induced increase in NFκB activity in both hemispheres. Histologic analysis of long-term cerebral damage revealed that inhibition of NFκB activation by administration of NBD peptide at 0, 6, and 12 h after HI resulted in an increment of neuronal damage. In conclusion, our data suggest that inhibition of NFκB activation using NBD peptide early after HI increases brain damage in neonatal rats.

/pdf/selective-inhibition-of-nuclear-factor-kb-activation-after-33vg4hsy0p.pdf

Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective

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Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective