MiR-182 Inhibition Protects Against Experimental Stroke in vivo and Mitigates Astrocyte Injury and Inflammation in vitro via Modulation of Cortactin Activity

Neurochem Res. 2022 Dec;47(12):3682-3696. doi: 10.1007/s11064-022-03718-6. Epub 2022 Aug 11.

Abstract

Ischemic stroke remains a devastating cerebrovascular disease that accounts for a high proportion of mortality and disability worldwide. MicroRNAs (miRNAs) are a class of small non-coding RNAs that are responsible for regulation of post-transcriptional gene expression, and growing evidence supports a role for miRNAs in stroke injury and recovery. The current study examined the role of miR-182 in experimental stroke using both in vitro and in vivo models of ischemic injury. Brain levels of miR-182 significantly increased after transient middle cerebral artery occlusion (MCAO) in mice and in primary astrocyte cultures subjected to combined oxygen-glucose deprivation/reperfusion (OGD/R) injury. In vivo, stroke volume and neurological score were significantly improved by pre-treatment with miR-182 antagomir. Astrocyte cultures stressed with OGD/R resulted in mitochondrial fragmentation and downregulation of cortactin, an actin-binding protein. Inhibition of miR-182 significantly preserved cortactin expression, reduced mitochondrial fragmentation and improved astrocyte survival after OGD/R. In parallel, lipopolysaccharide (LPS)-induced nitric-oxide release in astrocyte cultures was significantly reduced by miR-182 inhibition, translating to reduced injury in primary neuronal cultures subjected to conditioned medium from LPS-treated astrocytes. These findings identify miR-182 and/or cortactin as potential clinical targets to preserve mitochondrial structure and mitigate neuroinflammation and cell death after ischemic stroke.

Keywords: Cerebral ischemia; Cytoskeleton; Glia; Mitochondria; Oxidative stress; microRNA.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Astrocytes / metabolism
  • Brain Ischemia* / metabolism
  • Cortactin / metabolism
  • Glucose
  • Inflammation / genetics
  • Inflammation / prevention & control
  • Ischemic Stroke
  • Lipopolysaccharides
  • Mice
  • MicroRNAs* / metabolism
  • Oxygen / metabolism
  • Reperfusion Injury* / metabolism
  • Stroke* / genetics
  • Stroke* / prevention & control

Substances

  • Cortactin
  • Glucose
  • Lipopolysaccharides
  • MicroRNAs
  • Oxygen
  • Mirn182 microRNA, mouse