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(Stroke. 2008;39:2578.)
© 2008 American Heart Association, Inc.

Original Contributions

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

Cora H. Nijboer, MSc; Cobi J. Heijnen, PhD; Floris Groenendaal, MD, PhD; Michael J. May, PhD; Frank van Bel, MD, PhD Annemieke Kavelaars, PhD

From the Laboratory of Psychoneuroimmunology (C.H.N., C.J.H., A.K.) and the Department of Neonatology (C.H.N., F.G., F.v.B.), University Medical Center Utrecht, The Netherlands; and the Department of Animal Biology (M.J.M.), University of Pennsylvania, School of Veterinary Medicine, Philadelphia.

Correspondence to Dr Cobi J. Heijnen, Professor of Psychoneuroimmunology, University Medical Center Utrecht, KC03.068.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail C.Heijnen{at}umcutrecht.nl

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.

Key Words: nuclear factor-B • inflammation • neonatal • neuroprotection • apoptosis • ischemia

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