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J Biol Chem. 2015 Dec 11;290(50):30042-52. doi: 10.1074/jbc.M115.673525. Epub 2015 Oct 23.

The Blockade of NF-κB Activation by a Specific Inhibitory Peptide Has a Strong Neuroprotective Role in a Sprague-Dawley Rat Kernicterus Model.

Author information

1
From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, 400000, China.
2
From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Key Laboratory of Pediatrics in Chongqing, Chongqing, 400000, China, and.
3
From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China.
4
From the Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, 400000, China, the Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400000, China, the Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400000, China h_ziyu@163.com.

Abstract

Kernicterus, the permanent nerve damage occurring as a result of bilirubin precipitation, still occurs worldwide and may lead to death or permanent neurological impairments. However, the underlying mechanisms remain unclear, and effective therapeutic strategies are lacking. The present study aims to investigate the activation of NF-κB and to identify the effect of NF-κB inhibition on the newborn rat kernicterus model. The NF-κB essential modifier-binding domain peptide (NBD), coupled with the HIV trans-activator of transcription peptide (TAT) was used to inhibit NF-κB. NF-κB was significantly activated in the cerebrum at 1 and 3 h (p < 0.05) after the model was established, as measured by EMSA. NF-κB activation was inhibited by intraperitoneal administration of TAT-NBD. The general conditions of the TAT-NBD-treated rats were improved; meanwhile, these rats performed much better on the neurological evaluation, the rotarod test, and the Morris water maze test (p < 0.05) than the vehicle-treated rats at 28 days. Furthermore, the morphology of the nerve cells was better preserved in the TAT-NBD group, and these cells displayed less neurodegeneration and astrocytosis. Simultaneously, apoptosis in the brain was attenuated, and the levels of the TNF-α and IL-1β proteins were decreased (p < 0.01). These results suggested that NF-κB was activated, and inhibition of NF-κB activation by TAT-NBD not only attenuated the acute neurotoxicity, apoptosis, and inflammation, but also improved the long term neurobehavioral impairments in the kernicterus model rats in vivo. Thus, inhibiting NF-κB activation might be a potential therapeutic approach for kernicterus.

KEYWORDS:

NF-kappaB; TAT-NBD; bilirubin encephalopathy; kernicterus; neuroinflammation; neurological disease; neuroprotection; neuroprotective; neuroscience

PMID:
26499797
PMCID:
PMC4706004
DOI:
10.1074/jbc.M115.673525
[Indexed for MEDLINE]
Free PMC Article

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