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NF-?B signaling pathway inhibition suppresses hippocampal neuronal apoptosis and cognitive impairment via RCAN1 in neonatal rats with hypoxic-ischemic brain damage.

ABSTRACT: NF-?B is a core transcription factor, the activation of which can lead to hypoxic-ischemic brain damage (HIBD), while RCAN1 plays a protective role in HIBD. However, the relationship between NF-?B and RCAN1 in HIBD remains unclear. This study aimed to explore the mechanism of NF-?B signaling pathway in hippocampal neuron apoptosis and cognitive impairment of neonatal rats with HIBD in relation to RCAN1. Initially, microarray analysis was used to determine the differentially expressed genes related to HIBD. After the establishment of HIBD rat models, gain- or loss-of-function assay was performed to explore the functional role of NF-?B signaling pathway in HIBD. Then, the learning and memory ability of rats was evaluated. Expression of RCAN1, NF-?B signaling pathway-related genes and glial fibrillary acidic protein (GFAP), S-100? and acetylcholine (Ach) level, and acetylcholinesterase (AchE) activity were determined with neuron apoptosis detected to further explore the function of NF-?B signaling pathway. RCAN1 could influence the development of HIBD. In the HIBD model, the expression of RCAN1 and NF-?B-related genes increased, and NF-?B p65 showed a significant nuclear shift. By activation of NF-?B or overexpression of RCAN1, the number of neuronal apoptosis, S-100? protein level, and AchE level increased significantly, Ach activity decreased significantly, and GFAP positive cells increased. In addition, after the activation of NF-?B or overexpression of RCAN1, the learning and memory ability of HIBD rats was inhibited. All the results show that activation of NF-?B signaling pathway promotes RCAN1 expression, thus increasing neuronal apoptosis and aggravating cognitive impairment in HIBD rats.

SUBMITTER: Fang H

PROVIDER: S-EPMC6527272 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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NF-κB signaling pathway inhibition suppresses hippocampal neuronal apoptosis and cognitive impairment via RCAN1 in neonatal rats with hypoxic-ischemic brain damage.

Fang Hua H Li Hua-Feng HF Yang Miao M Liao Ren R Wang Ru-Rong RR Wang Quan-Yun QY Zheng Peng-Cheng PC Zhang Fang-Xiang FX Zhang Jian-Ping JP

Cell cycle (Georgetown, Tex.) 20190503 9

NF-κB is a core transcription factor, the activation of which can lead to hypoxic-ischemic brain damage (HIBD), while RCAN1 plays a protective role in HIBD. However, the relationship between NF-κB and RCAN1 in HIBD remains unclear. This study aimed to explore the mechanism of NF-κB signaling pathway in hippocampal neuron apoptosis and cognitive impairment of neonatal rats with HIBD in relation to RCAN1. Initially, microarray analysis was used to determine the differentially expressed genes relat ...[more]

PMID: 30990350

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Project description:BackgroundAngiogenesis is an endogenous repair mechanism following hypoxic-ischemic brain damage (HIBD). Interestingly, recent studies have shown that angiogenesis can be regulated by telomerase reverse transcriptase (TERT), a critical component of telomerase. As telomerase reverse transcriptase can promote angiogenesis after stroke, we hypothesized that it could also promote angiogenesis after HIBD. To test this hypothesis, we developed in vivo and in vitro HIBD models in neonatal rats.MethodsTERT was overexpressed by lentivirus and adenovirus infection, and levels were measured using quantitative real-time polymerase chain reaction. We used a cell counting kit to quantify the proliferation rate of brain microvascular endothelial cells (BMECs), and immunofluorescence staining to measure CD34 expression levels. A microvessel formation assay was used to evaluate angiogenesis. Blood-brain barrier (BBB) integrity was assessed using immunohistochemical staining for ZO-1 and Evans Blue staining. Lastly, the expression level of Notch-1 was measured by western blotting.ResultsOverexpression of TERT promoted the proliferation of BMECs after hypoxic-ischemic damage in vitro. TERT overexpression increased the formation of microvessels in the neonatal brain after HIBD both in vivo and in vitro. Overexpression of TERT improved BBB integrity in the brains of neonatal rats after HIBD. In addition, the expression level of Notch-1 was increased in BMECs following oxygen glucose deprivation, and overexpression of TERT further increased Notch-1 expression levels in BMECs following oxygen glucose deprivation.DiscussionOur results reveal that telomerase reverse transcriptase promotes angiogenesis and maintains the integrity of the blood-brain barrier after neonatal hypoxic-ischemic brain damage. Furthermore, the Notch-1 signaling pathway appears to contribute to the angiogenic function of telomerase reverse transcriptase. This protective effect of telomerase reverse transcriptase opens new horizons for future investigations aimed at uncovering the full potential of telomerase reverse transcriptase as a promising new target for the treatment of hypoxic-ischemic encephalopathy.

Dataset Information

NF-?B signaling pathway inhibition suppresses hippocampal neuronal apoptosis and cognitive impairment via RCAN1 in neonatal rats with hypoxic-ischemic brain damage.

Publications

NF-κB signaling pathway inhibition suppresses hippocampal neuronal apoptosis and cognitive impairment via RCAN1 in neonatal rats with hypoxic-ischemic brain damage.

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