title: 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.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Psychology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Nikita M
authors.initials: NM
authors.lastname: Bajwa
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Fuxia
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Neonatology, Loma Linda University Children's Hospital, Loma Linda, CA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Harding
authors.affiliation: Department of Psychology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hartman
authors.affiliation: 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.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000517:prevention & control*; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009841:Oligonucleotides / Q000008:administration & dosage*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C546388:MIRN210 microRNA, rat; D035683:MicroRNAs; D018696:Neuroprotective Agents; D009841:Oligonucleotides; D011965:Receptors, Glucocorticoid; C477371:locked nucleic acid
keywords: Complementary locked nucleic acid (LNA) oligonucleotides; Glucocorticoid receptor; Intranasal delivery; MicroRNA-210; Neonatal hypoxic–ischemic brain injury; Neuroprotection