Strong Neuroprotection by Inhibition of NF-κB After Neonatal Hypoxia-Ischemia Involves Apoptotic Mechanisms but Is Independent of Cytokines

• Published in: Stroke (1970) 2008-07, Vol.39 (7), p.2129-2137
• Main Authors: NIJBOER, Cora H. A, HEIJNEN, Cobi J, GROENENDAAL, Floris, MAY, Michael J, VAN BEL, Frank, KAVELAARS, Annemieke
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.107.504175

Background and Purpose— Interactions between excitotoxic, inflammatory, and apoptotic pathways determine outcome in hypoxic-ischemic brain damage. The transcription factor NF-κB has been suggested to enhance brain damage via stimulation of cytokine production. There is also evidence that NF-κB activity is required for neuronal survival. We used the NF-κB inhibitor NBD, coupled to TAT to facilitate cerebral uptake, to determine the neuroprotective capacity of NF-κB inhibition in neonatal hypoxia-ischemia (HI) and to identify its contribution to cerebral inflammation and damage. Methods— Brain damage was induced in neonatal rats by unilateral carotid artery occlusion and hypoxia and analyzed immunohistochemically; NF-κB activity was analyzed by EMSA. We analyzed cytokine mRNA levels and activation of apoptotic pathways by Western blotting. In vitro effects of TAT-NBD were determined in a neuronal cell line. Results— Inhibition of cerebral NF-κB activity by TAT-NBD had a significant neuroprotective effect; brain damage was reduced by more than 80% with a therapeutic window of at least 6 hours. In contrast to earlier suggestions, the protective effect of TAT-NBD did not involve suppression of early cytokine upregulation after HI. Moreover, NF-κB inhibition prevented HI-induced upregulation and nuclear as well as mitochondrial accumulation of p53, prevented mitochondrial cytochrome- c release and activation of caspase-3. Finally, TAT-NBD could directly increase neuronal survival because TAT-NBD was sufficient to inhibit death in a neuronal cell line. A nonactive mutant peptide did not have any effect. Conclusions— Inhibition of NF-κB has strong neuroprotective effects that involve downregulation of apoptotic molecules but are independent of inhibition of cytokine production.