Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats

Abstract

Because our recent studies have demonstrated that miR-122 decreased in whole blood of patients and in whole blood of rats following ischemic stroke, we tested whether elevating blood miR-122 would improve stroke outcomes in rats. Young adult rats were subjected to a temporary middle cerebral artery occlusion (MCAO) or sham operation. A polyethylene glycol-liposome-based transfection system was used to administer a miR-122 mimic after MCAO. Neurological deficits, brain infarction, brain vessel integrity, adhesion molecule expression and expression of miR-122 target and indirect-target genes were examined in blood at 24 h after MCAO with or without miR-122 treatment. miR-122 decreased in blood after MCAO, whereas miR-122 mimic elevated miR-122 in blood 24 h after MCAO. Intravenous but not intracerebroventricular injection of miR-122 mimic decreased neurological deficits and brain infarction, attenuated ICAM-1 expression, and maintained vessel integrity after MCAO. The miR-122 mimic also down-regulated direct target genes (e.g. Vcam1, Nos2, Pla2g2a) and indirect target genes (e.g. Alox5, Itga2b, Timp3, Il1b, Il2, Mmp8) in blood after MCAO which are predicted to affect cell adhesion, diapedesis, leukocyte extravasation, eicosanoid and atherosclerosis signaling. The data show that elevating miR-122 improves stroke outcomes and we postulate this occurs via downregulating miR-122 target genes in blood leukocytes.

Non-coding RNAs and neuroprotection after acute CNS injuries

“…The lesser known role of caspase-3 in regulating microglial activation without triggering cell death through a protein kinase C dependent pathway might have played a role in this particular response (Burguillos et al, 2011). Replenishing miR-122 levels by intravenous administration of a miR-122 mimic was shown to reduce neurological deficits, infarct volume and ICAM-1 expression together with downregulation of direct and indirect target genes and maintenance of vascular integrity in a rat model of focal ischemia by acting on blood leukocytes rather than the brain tissue directly (Liu et al, 2016a) (Fig. 1).…”

Stroke Recovery Genetics

“…However, some examples can be mentioned: animal model results support the presence of genetic determinants of outcome 53 and indicate genetic impact on cerebrovascular collateral density and infarct lesion size. 54 Animal models can also examine if genetic variations detected in humans have an impact on poststroke outcome.…”

“…Epigenetic mechanisms regulating the DNA transcription have a potential role in stroke recovery and can modulate several downstream pathways-for review see Elder et al 62 Micro-RNA in an ischemic brain area can be up-and downregulated during different time points of the spontaneous recovery phase of ischemic stroke, 53 indicating how different biochemical pathways are controlled. Genetic influence on epigenetic mechanisms and epigenetic influence on genetic expression are potentially important targets for understanding and enhancing stroke recovery.…”

MicroRNA-15a/16-1 Antagomir Ameliorates Ischemic Brain Injury in Experimental Stroke

“…injections effectively improves stroke outcomes via downregulating miR-122 target genes in blood leukocytes in rats. 35 …”