A dual role of the NF-κB pathway in neonatal hypoxic-ischemic brain damage
A dual role of the NF-κB pathway in neonatal hypoxic-ischemic brain damage
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DOI：
10.1161/strokeaha.108.516401
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发表时间：
2008-09-01
期刊：
影响因子：
8.3
通讯作者：
Kavelaars, Annemieke
中科院分区：
文献类型：
--
作者：
Nijboer, Cora H.;Heijnen, Cobi J.;Kavelaars, Annemieke
背景和目的--核因子-kappaB是一种转录因子，调节炎症和细胞凋亡途径。我们以前描述过，在新生儿缺氧缺血(HI)后0小时和3小时，腹腔注射核因子-kappaB抑制剂TAT-NBD可显著减少脑损伤。我们推测，抑制核因子-kappaB的时间和持续时间将是决定结果的主要因素。方法采用单侧颈动脉结扎和低氧诱导P7大鼠的-HI。体内测定TAT-NBD对脑损伤、核因子-kappaB活性、细胞因子表达、促凋亡和抗凋亡分子的影响。结果HI3~6h和2 4h诱导脑组织核因子-kappaB活性出现2个高峰。神经保护作用0/3h的TAT-NBD仅抑制早期核因子-kappaB的活性。然而，0/6/12小时的TAT-NBD或18/21小时的TAT-NBD仅抑制晚期的核因子-kappaB活性会加重损伤。0/6/12小时TAT-NBD不能阻止HI后24小时细胞因子的上调。保护性的0/3小时TAT-NBD治疗可阻止缺氧缺血后24小时P53的核积聚。0/6/12小时TAT-NBD后，核P53蛋白表达未见减少。延长TAT-NBD可增加促凋亡因子PUMA，降低抗凋亡因子Bcl2和Bclxl。此外，在神经元培养中，长期的TAT-NBD暴露排除了保护性的短期TAT-NBD治疗。结论-早期核因子-kappaB的激活参与了新生儿HI脑损伤。晚期核因子-kappaB提供内源性神经保护并上调抗凋亡分子。只有在维持晚期核因子-kappaB活性的情况下，抑制早期核因子-kappaB的活性才具有神经保护作用。此外，脑细胞因子的产生不依赖于核因子-kappaB。
Background and Purpose - NF-kappa B is a transcription factor that regulates inflammatory and apoptotic pathways. We described previously that intraperitoneal administration of the NF-kappa 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-kappa 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-kappa 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-kappa B activity at 3 to 6 and 24 hours after HI. Neuroprotective 0/3-hour TAT-NBD treatment only inhibited early NF-kappa B activity. However, inhibition of both early and late NF-kappa B-activity by 0/6/12-hour TAT-NBD or only late NF-kappa 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-kappa B activation contributes to neonatal HI brain damage. Late NF-kappa B provides endogenous neuroprotection and upregulates antiapoptotic molecules. Inhibition of early NF-kappa B activity is neuroprotective only when late NF-kappa B activity is maintained. Moreover, cerebral cytokine production can occur independently of NF-kappa B.