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Neurobiol Dis. 2016 May;89:202-12. doi: 10.1016/j.nbd.2016.02.011. Epub 2016 Feb 11.

Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats.

Author information

1
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
2
Department of Psychology, Loma Linda University, Loma Linda, CA, USA.
3
Department of Neonatology, Loma Linda University Children's Hospital, Loma Linda, CA, USA.
4
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: lzhang@llu.edu.

Abstract

Perinatal hypoxic-ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. Yet the mechanisms of brain injury in infants with HIE remain largely elusive. The present study determined a novel mechanism of microRNA-210 (miR-210) in silencing endogenous neuroprotection and increasing hypoxic-ischemic brain injury in neonatal rats. The study further revealed a potential therapeutic effect of miR-210 inhibition using complementary locked nucleic acid oligonucleotides (miR-210-LNA) in 10-day-old neonatal rats in the Rice-Vannucci model. The underlying mechanisms were investigated with intracerebroventricular injection (i.c.v) of miR-210 mimic, miR-210-LNA, glucocorticoid receptor (GR) agonist and antagonist. Luciferase reporter gene assay was conducted for identification of miR-210 targeting GR 3'untranslated region. The results showed that the HI treatment significantly increased miR-210 levels in the brain, and miR-210 mimic significantly decreased GR protein abundance and exacerbated HI brain injury in the pups. MiR-210-LNA administration via i.c.v. 4h after the HI insult significantly decreased brain miR-210 levels, increased GR protein abundance, reduced HI-induced neuronal death and brain infarct size, and improved long-term neurological function recovery. Of importance, the intranasal delivery of miR-210-LNA 4h after the HI insult produced similar effects in decreasing HI-induced neonatal brain injury and improving neurological function later in life. Altogether, the present study provides evidence of a novel mechanism of miR-210 in a neonatal HI brain injury model, and suggests a potential therapeutic approach of miR-210 inhibition in the treatment of neonatal HIE.

KEYWORDS:

Complementary locked nucleic acid (LNA) oligonucleotides; Glucocorticoid receptor; Intranasal delivery; MicroRNA-210; Neonatal hypoxic–ischemic brain injury; Neuroprotection

PMID:
26875527
PMCID:
PMC4785034
DOI:
10.1016/j.nbd.2016.02.011
[Indexed for MEDLINE]
Free PMC Article

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