A dual role of the nf-kappa b pathway in neonatal hypoxic-ischemic brain damage

BACKGROUND AND PURPOSE: NF-kB is a transcription factor that regulates inflammatory and apoptotic pathways. We described previously that intraperitoneal administration of the NF-kB inhibitor TAT-NBD at 0 and 3 hours after neonatal hypoxia-ischemia (HI) markedly reduced brain damage. We hypothesize that timing and duration of NF-kB inhibition will be a major factor in determining outcome. METHODS: HI was induced in P7 rats by unilateral carotid artery occlusion and hypoxia. In vivo TAT-NBD effects were determined on cerebral damage, NF-kB activity, cytokine expression, and pro- and antiapoptotic molecules. In vitro effects of TAT-NBD were determined using primary neurons and cell lines. RESULTS: HI induced 2 peaks of cerebral NF-kB activity at 3 to 6 and 24 hours after HI. Neuroprotective 0/3-hour TAT-NBD treatment only inhibited early NF-kB activity. However, inhibition of both early and late NF-kB-activity by 0/6/12-hour TAT-NBD or only late NF-kB activity by 18/21-hour TAT-NBD aggravated damage. 0/6/12-hour TAT-NBD did not prevent HI-induced upregulation of cytokines at 24 hours after HI. Protective 0/3-hour TAT-NBD treatment prevented nuclear accumulation of p53 at 24 hours after HI. Nuclear p53 was not reduced after 0/6/12-hour TAT-NBD. Prolonged TAT-NBD increased the proapoptotic factor PUMA and reduced the antiapoptotic factors Bcl-2 and Bcl-xL. Also in neuronal cultures prolonged TAT-NBD exposure overruled protective short-term TAT-NBD treatment. CONCLUSIONS: Early NF-kB activation contributes to neonatal HI brain damage. Late NF-kB provides endogenous neuroprotection and upregulates antiapoptotic molecules. Inhibition of early NF-kB activity is neuroprotective only when late NF-kB activity is maintained. Moreover, cerebral cytokine production can occur independently of NF-kB.