A Dual Role of the NF- B Pathway in Neonatal Hypoxic-Ischemic Brain Damage

Background and Purpose—NFB is a transcription factor that regulates inflammatory and apoptotic pathways. We described previously that intraperitoneal administration of the NFB inhibitor TAT-NBD at 0 and 3 hours after neonatal hypoxia-ischemia (HI) markedly reduced brain damage. We hypothesize that timing and duration of NFB 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, NFB activity, cytokine expression, and proand antiapoptotic molecules. In vitro effects of TAT-NBD were determined using primary neurons and cell lines. Results—HI induced 2 peaks of cerebral NFB activity at 3 to 6 and 24 hours after HI. Neuroprotective 0/3-hour TAT-NBD treatment only inhibited early NFB activity. However, inhibition of both early and late NFB-activity by 0/6/12-hour TAT-NBD or only late NFB 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 NFB activation contributes to neonatal HI brain damage. Late NFB provides endogenous neuroprotection and upregulates antiapoptotic molecules. Inhibition of early NFB activity is neuroprotective only when late NFB activity is maintained. Moreover, cerebral cytokine production can occur independently of NFB. (Stroke. 2008;39:2578-2586.)