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Int. J. Mol. Sci. 2017, 18(7), 1356; doi:10.3390/ijms18071356

MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury

Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA
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Received: 27 May 2017 / Revised: 21 June 2017 / Accepted: 22 June 2017 / Published: 24 June 2017
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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Abstract

Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain. miR-210 mimic was administered via intracerebroventricular injection (i.c.v.) into the brain of rat pups. Forty-eight hours after the injection, a modified Rice-Vannucci model was conducted to produce HI brain injury. Post-assays included cerebral edema analysis, western blotting, and immunofluorescence staining for serum immunoglobulin G (IgG) leakage. The results showed that miR-210 mimic exacerbated cerebral edema and IgG leakage into the brain parenchyma. In contrast, inhibition of miR-210 with its complementary locked nucleic acid oligonucleotides (miR-210-LNA) significantly reduced cerebral edema and IgG leakage. These findings suggest that miR-210 negatively regulates BBB integrity i n the neonatal brain. Mechanistically, the seed sequences of miR-210 were identified complementary to the 3′ untranslated region (3′ UTR) of the mRNA transcripts of tight junction protein occludin and adherens junction protein β-catenin, indicating downstream targets of miR-210. This was further validated by in vivo data showing that miR-210 mimic significantly reduced the expression of these junction proteins in rat pup brains. Of importance, miR-210-LNA preserved the expression of junction proteins occludin and β-catenin from neonatal HI insult. Altogether, the present study reveals a novel mechanism of miR-210 in impairing BBB integrity that contributes to cerebral edema formation after neonatal HI insult, and provides new insights in miR-210-LNA mediated neuroprotection in neonatal HI brain injury. View Full-Text
Keywords: neonatal hypoxic-ischemic brain injury; microRNA-210; blood-brain barrier integrity; cerebral edema neonatal hypoxic-ischemic brain injury; microRNA-210; blood-brain barrier integrity; cerebral edema
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MDPI and ACS Style

Ma, Q.; Dasgupta, C.; Li, Y.; Huang, L.; Zhang, L. MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury. Int. J. Mol. Sci. 2017, 18, 1356.

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