Background and Purpose—NF-B is a transcription factor that regulates inflammatory and apoptotic pathways. We described previously that intraperitoneal administration of the NF-B 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-B 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-B 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-B activity at 3 to 6 and 24 hours after HI. Neuroprotective 0/3-hour TAT-NBD treatment only inhibited early NF-B activity. However, inhibition of both early and late NF-B-activity by 0/6/12-hour TAT-NBD or only late NF-B 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-B activation contributes to neonatal HI brain damage. Late NF-B provides endogenous neuroprotection and upregulates antiapoptotic molecules. Inhibition of early NF-B activity is neuroprotective only when late NF-B activity is maintained. Moreover, cerebral cytokine production can occur independently of NF-B.