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MicroRNA-9 mediated the protective effect of ferulic acid on hypoxic-ischemic brain damage in neonatal rats.

ABSTRACT: Neonatal hypoxic-ischemic brain damage (HIBD) is prone to cognitive and memory impairments, and there is no effective clinical treatment until now. Ferulic acid (FA) is found within members of the genus Angelica, reportedly shows protective effects on neuronal damage. However, the protective effects of FA on HIBD remains unclear. In this study, using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to HIBD was significantly reversed by FA treatment and the administration of LNA-miR-9. The expression of miRNA-9 was detected by RT-PCR analyses, and the results shown that miRNA-9 was significantly increased in the hippocampus of neonatal rats following HIBD and in the PC12 cells following hypoxic-ischemic injury, while FA and LNA-miR-9 both inhibited the expression of miRNA-9, suggesting that the therapeutic effect of FA was mainly attributed to the inhibition of miRNA-9 expression. Indeed, the silencing of miR-9 by LNA-miR-9 or FA similarly attenuated neuronal damage and cerebral atrophy in the rat hippocampus after HIBD, which was consistent with the restored expression levels of brain-derived neurotrophic factor (BDNF). Therefore, our findings indicate that FA treatment may protect against neuronal death through the inhibition of miRNA-9 induction in the rat hippocampus following hypoxic-ischemic damage.

SUBMITTER: Yao K

PROVIDER: S-EPMC7259979 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MicroRNA-9 mediated the protective effect of ferulic acid on hypoxic-ischemic brain damage in neonatal rats.

Yao Keli K Yang Qin Q Li Yajuan Y Lan Ting T Yu Hong H Yu Yang Y

PloS one 20200529 5

Neonatal hypoxic-ischemic brain damage (HIBD) is prone to cognitive and memory impairments, and there is no effective clinical treatment until now. Ferulic acid (FA) is found within members of the genus Angelica, reportedly shows protective effects on neuronal damage. However, the protective effects of FA on HIBD remains unclear. In this study, using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to HIBD was significantly reverse ...[more]

PMID: 32470970

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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.

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.

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MicroRNA-9 mediated the protective effect of ferulic acid on hypoxic-ischemic brain damage in neonatal rats.

Publications

MicroRNA-9 mediated the protective effect of ferulic acid on hypoxic-ischemic brain damage in neonatal rats.

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