A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage.
OBJECTIVE
NF-kappaB is a transcription factor that regulates inflammatory and apoptotic pathways. We described previously that intraperitoneal administration of the NF-kappaB 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-kappaB 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-kappaB 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-kappaB activity at 3 to 6 and 24 hours after HI. Neuroprotective 0/3-hour TAT-NBD treatment only inhibited early NF-kappaB activity. However, inhibition of both early and late NF-kappaB-activity by 0/6/12-hour TAT-NBD or only late NF-kappaB 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-kappaB activation contributes to neonatal HI brain damage. Late NF-kappaB provides endogenous neuroprotection and upregulates antiapoptotic molecules. Inhibition of early NF-kappaB activity is neuroprotective only when late NF-kappaB activity is maintained. Moreover, cerebral cytokine production can occur independently of NF-kappaB.
Nijboer
Cora H
CH
University Medical Center Utrecht, KC03.068.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
Heijnen
Cobi J
CJ
Groenendaal
Floris
F
May
Michael J
MJ
van Bel
Frank
F
Kavelaars
Annemieke
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D016159:Tumor Suppressor Protein p53