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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:Circadian rhythm disorder is a common, but often neglected, consequence of neonatal hypoxic-ischemic brain damage (HIBD). However, the underlying molecular mechanisms remain largely unknown. We previously showed that, in a rat model of HIBD, up-regulation of microRNA-325 (miR-325) in the pineal gland is responsible for the suppression of Aanat, a key enzyme involved in melatonin synthesis and circadian rhythm regulation. To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD, we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University (Dushuhu Branch) in 2019. We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD. Furthermore, a luciferase reporter gene assay revealed that LIM homeobox 3 (LHX3) is a novel downstream target of miR-325. In addition, in miR-325 knock-down mice, the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland. We established a neonatal mouse model of HIBD by performing double-layer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours. Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions. Finally, we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3. Taken together, our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD. The clinical trial was approved by Institutional Review Board of Children's Hospital of Soochow University (approval No. 2015028) on July 20, 2015. Animal experiments were approved by Animal Care and Use Committee, School of Medicine, Soochow University, China (approval No. XD-2016-1) on January 15, 2016.

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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