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

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.

• Authors: Qingyi Ma, Chiranjib Dasgupta, Yong Li, Nikita M Bajwa, Fuxia Xiong, Benjamin Harding, Richard Hartman, Lubo Zhang
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 89 Pg. 202-12 (May 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26875527 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• MIRN210 microRNA, rat
• MicroRNAs
• Neuroprotective Agents
• Oligonucleotides
• Receptors, Glucocorticoid
• locked nucleic acid

Topics

• 3' Untranslated Regions
• Animals
• Animals, Newborn
• Brain (metabolism)
• Hypoxia-Ischemia, Brain (metabolism, prevention & control)
• MicroRNAs (antagonists & inhibitors, metabolism)
• Neuroprotective Agents (administration & dosage)
• Oligonucleotides (administration & dosage)
• Rats
• Receptors, Glucocorticoid (agonists, antagonists & inhibitors, genetics, metabolism)