This Article Full Text Full Text (PDF) All Versions of this Article: 40/10/3362    most recent STROKEAHA.109.560250v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Nijboer, C. H. Articles by Kavelaars, A. PubMed PubMed Citation Articles by Nijboer, C. H. Articles by Kavelaars, A. Related Collections Animal models of human disease Neuroprotectors

(Stroke. 2009;40:3362.)
© 2009 American Heart Association, Inc.

Original Contributions

Alternate Pathways Preserve Tumor Necrosis Factor- Production After Nuclear Factor-B Inhibition in Neonatal Cerebral Hypoxia–Ischemia

Cora H. Nijboer, PhD; Cobi J. Heijnen, PhD; Floris Groenendaal, MD, 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 (F.G., F.v.B.), University Medical Center Utrecht, Utrecht, The Netherlands.

Correspondence to Cobi J. Heijnen, PhD, 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— Nuclear factor-B (NF-B) is an important regulator of inflammation and apoptosis. We showed previously that NF-B inhibition by intraperitoneal TAT-NBD treatment strongly reduced neonatal hypoxic–ischemic (HI) brain damage. Neuroprotection by TAT-NBD was not associated with inhibition of cerebral cytokine production. We investigated how tumor necrosis factor- (TNF-) production is maintained after NF-B inhibition and whether TNF- contributes to brain damage.

Methods— Postnatal Day 7 rats were subjected to unilateral carotid artery occlusion and hypoxia. Rats were treated immediately after HI with TAT-NBD, the JNK inhibitor TAT-JBD, and/or the TNF- inhibitor etanercept. We determined brain damage, NF-B and AP-1 activity, Gadd45β, XIAP, (P-)TAK1, TNF-, and TNF receptor expression.

Results— Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNF- production. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45β, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-B and JNK/AP-1 abrogated HI-induced TNF- production. However, this treatment reduced the neuroprotective effect of NF-B inhibition alone. We show that etanercept was detectable in the HI brain after intraperitoneal administration and that etanercept treatment also reduced the neuroprotective effect of NF-B inhibition. Finally, NF-B inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression.

Conclusions— When NF-B was inhibited after neonatal cerebral HI, JNK/AP-1 activity was increased and required for increased TNF- expression. Our data indicate that the switch to JNK/AP-1 activation preserves HI-induced TNF- expression and thereby might contribute to the neuroprotective effect of TAT-NBD possibly through a TNF-R2 dependent mechanism.

Key Words: JNK • neonatal ischemia • neuroprotection • NF-B • TNF-