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

Background and Purpose—Nuclear factorB (NFB) is an important regulator of inflammation and apoptosis. We showed previously that NFB 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 NFB inhibition and whether TNFcontributes 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 TNFinhibitor etanercept. We determined brain damage, NFB and AP-1 activity, Gadd45 , XIAP, (P-)TAK1, TNF, and TNF receptor expression. Results—Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNFproduction. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45 , XIAP, and increased (P)-TAK1 expression. Combined inhibition of NFB and JNK/AP-1 abrogated HI-induced TNFproduction. However, this treatment reduced the neuroprotective effect of NFB 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 NFB inhibition. Finally, NFB inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression. Conclusions—When NFB was inhibited after neonatal cerebral HI, JNK/AP-1 activity was increased and required for increased TNFexpression. Our data indicate that the switch to JNK/AP-1 activation preserves HI-induced TNFexpression and thereby might contribute to the neuroprotective effect of TAT-NBD possibly through a TNF-R2 dependent mechanism. (Stroke. 2009;40:3362-3368.)