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

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-B and to identify the effect of NF-B inhibition on the newborn rat kernicterus model. The NF-B essential modifier-binding domain peptide (NBD), coupled with the HIV trans-activator of transcription peptide (TAT) was used to inhibit NF-B. NF-B was significantly activated in the cerebrum at 1 and 3 h (p < 0.05) after the model was established, as measured by EMSA. NF-B 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-␣ and IL-1␤ proteins were decreased (p < 0.01). These results suggested that NF-B was activated, and inhibition of NF-B 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-B activation might be a potential therapeutic approach for kernicterus.

Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes

“…Notably, astrocytes, as the most abundant type of glial cells, are key mediators involved in the inflammatory responses in several CNS diseases [ 14 ]. Recently, several in vitro and in vivo studies have indicated that UCB-activated astrocytes release a variety of pro-inflammation cytokines, such as IL-1β and TNF-α, and eventually undergo time-dependent cell death [ 5 , 7 , 15 – 17 , 34 , 35 ]. Subsequently, these neuroinflammatory molecules released by active astrocytes induce recruitment and activation of additional glial cells secreting neuroinflammatory molecules, causing further cell damage [ 16 ].…”

“…Recent studies have demonstrated that elevated levels of UCB activated astrocytes and microglia, as well as gliosis, with a subsequent upregulation of inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 [ 15 – 18 ]. In turn, the increased cytokines could further exacerbate nerve cell death and inflammatory responses by activating the MAPK and nuclear factor-kappaB (NF-κB) signaling cascades [ 17 , 19 , 20 ]. Interestingly, blocking pro-inflammatory cytokine production decreased UCB-induced cell death, either by the loss of membrane integrity or by apoptosis [ 7 , 16 , 17 ].…”

“…In turn, the increased cytokines could further exacerbate nerve cell death and inflammatory responses by activating the MAPK and nuclear factor-kappaB (NF-κB) signaling cascades [ 17 , 19 , 20 ]. Interestingly, blocking pro-inflammatory cytokine production decreased UCB-induced cell death, either by the loss of membrane integrity or by apoptosis [ 7 , 16 , 17 ]. Thus, there may be a link between inflammation responses and nerve cell death caused by UCB, but the precise mechanism remains unclear.…”

Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway

“…We also observed that UA reduced the expression of Iba1, associated with evidence of microglial activation. Previous studies have shown that TLR4 is a key signaling pathway involved in ischemic penumbral microglial activation, which may be involved in the pathological cerebral conditions by upregulating NFκB ( 41 , 42 ). In the present study, we examined the levels of NFκB pathway components.…”

Baicalein inhibits TNF-α-induced NF-κB activation and expression of NF-κB-regulated target gene products

“…In the resting state, the inactive NF-κB is retained in the cytoplasm by an inhibitory subunit called IκB. The phosphorylation of IκB by the IκB-kinase (IKK) containing IKKα, IKKβ and the regulatory protein NF-κB essential modifier (NEMO) is a key step in NF-κB activation in response to various stimuli such as tumor necrosis factor-α (TNF-α) (3,4). In response to stimulation, IκBs are rapidly ubiquitinated and degraded by 26S proteasome complex and the release of IκB unmasks the nuclear localization signal and results in the translocation of NF-κB to the nucleus where it can bind to κB sites, followed by the activation of specific target genes (5).…”