title: MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia.
abstract: microRNA-124 (miR-124), the most abundant miRNA of the CNS, was recently shown to modulate the polarization of activated microglia and infiltrating macrophages towards the anti-inflammatory M2 phenotype and protect neurons in various ways after brain disease. In ischemic stroke, microglia and macrophages of a detrimental and persistent pro-inflammatory M1 phenotype have been shown to aggravate the secondary injury. Thus, shifting the polarization of microglia/macrophages into the beneficial, anti-inflammatory M2-like phenotype is considered neuroprotective after stroke onset. Here, we have induced 30 min transient occlusion of the right middle cerebral artery (MCAO) in 34 male, C57BL/6 mice. Lesion development was monitored with T2-weighted MRI. Liposomated miR-124 was injected in 11 animals at 48 h and in 5 animals at 10 days after MCAO. Arg-1, a marker for M2 phenotype, was co-stained with Iba-1, NeuN or GFAP. The distribution of astrocytes, neurons and microglia/macrophages and their expression of Arg-1 were quantified. Early miR-124 injection resulted in a significantly increased neuronal survival and a significantly increased number of M2-like polarized microglia/macrophages. Moreover, the lesion core, delineated by reactive astrocytes, was significantly reduced over time upon early miR-124 injection. These neuroprotective and anti-inflammatory effects of the early miR-124 treatment were pronounced during the first week with Arg-1. Number of Arg-1+ microglia/macrophages correlated with neuronal protection and with functional improvement during the first week. Thus, our present results demonstrate that miR-124 may serve as a novel therapeutic strategy for neuroprotection and functional recovery upon stroke onset.
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Hamzei Taj
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany.
authors.forename: Widuri
authors.initials: W
authors.lastname: Kho
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany; Percuros B.V., Enschede, The Netherlands.
authors.forename: Adrien
authors.initials: A
authors.lastname: Riou
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wiedermann
authors.affiliation: In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany; Dept. of Radiology, Leiden University Medical Center, Leiden, The Netherlands; Percuros B.V., Enschede, The Netherlands. Electronic address: mathias@sf.mpg.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hoehn
mesh_terms: D000818:Animals; D001119:Arginase / Q000032:analysis; D001921:Brain / Q000473:pathology*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000628:therapy*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000627:therapeutic use*; D017628:Microglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D000066829:Neuroprotection
chemical_list: D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: Arginase-1; Functional improvement; Immune cell modulation/polarization; Ischemic stroke; Neuroprotection; microRNA-124