Systemic antimiR-337-3p delivery inhibits cerebral ischemia-mediated injury

Neurobiol Dis. 2017 Sep;105:156-163. doi: 10.1016/j.nbd.2017.04.018. Epub 2017 Apr 28.

Abstract

Modulation of miRNA expression has been shown to be beneficial in the context of multiple diseases. The purpose of this study was to determine if an inhibitor of miR-337-3p is neuroprotective for hypoxic injury after tail vein injection. We evaluated miR-337-3p expression levels and in brain tissue in vivo before and after permanent middle cerebral artery occlusion (pMCAO) in mice. Subsequently, a custom locked nucleic acid (LNA) antimir-337-3p oligonucleotide was developed and tested in vitro after induction of oxygen glucose-deprivation (OGD) and in vivo by injection into the mouse tail vein for 3 consecutive days before pMCAO. Ischemic lesion volume was measured by TTC staining. We show that systemically administered LNA antimir-337-3p crosses the blood brain-brain-barrier (BBB), penetrates into neurosn, downregulates endogenous miR-337-3p expression and reduces ischemic brain injury. The findings support the use of similar antimir-LNA constructs as novel therapies in neurological disease.

Keywords: Anti-mRNA; LNA; Neuroprotection; Stroke; Systemic delivery; microRNA.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antibodies / administration & dosage*
  • Blood Pressure / drug effects
  • Brain Injuries / drug therapy*
  • Brain Injuries / etiology*
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Disease Models, Animal
  • Glucose / deficiency
  • Hypoxia / drug therapy
  • Infarction, Middle Cerebral Artery / complications*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Neurologic Examination
  • Neurons / drug effects
  • Oligonucleotides / therapeutic use
  • Time Factors

Substances

  • Antibodies
  • MicroRNAs
  • Mirn337 microRNA, human
  • Oligonucleotides
  • Caspases
  • Glucose