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A Rat Model of Middle Cerebral Artery Occlusion/Reperfusion Without Damaging the Anatomical Structure of Cerebral Vessels
Published on: May 17, 2024
Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats
Da Zhi Liu1, Glen C Jickling2, Bradley P Ander2
1Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, CA, USA dzliu@ucdavis.edu.
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.
Insights
Elevating miR-122 levels in the blood after ischemic stroke in rats improved stroke outcomes. This microRNA therapy reduced neurological deficits and brain infarction by targeting specific genes involved in inflammation and cell adhesion.
Area of Science:
- Biomedical research
- Molecular biology
- Stroke research
Background:
- MicroRNA-122 (miR-122) levels decrease in blood following ischemic stroke.
- Investigating miR-122's role in stroke pathophysiology is crucial for therapeutic development.
Purpose of the Study:
- To determine if increasing blood miR-122 levels can improve outcomes after ischemic stroke in rats.
- To elucidate the molecular mechanisms underlying miR-122's effects on stroke.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in rats to induce ischemic stroke.
- Administration of a miR-122 mimic using a liposome-based system.
- Assessment of neurological deficits, infarct volume, vascular integrity, adhesion molecules, and gene expression in blood.
Main Results:
- miR-122 mimic treatment significantly reduced neurological deficits and brain infarction.
- Intravenous miR-122 mimic administration maintained blood vessel integrity and attenuated ICAM-1 expression.
- miR-122 mimic down-regulated key target genes in blood leukocytes, impacting cell adhesion and inflammatory pathways.
Conclusions:
- Elevating blood miR-122 levels represents a promising therapeutic strategy for ischemic stroke.
- The therapeutic effects are likely mediated by the downregulation of miR-122 target genes in blood cells, modulating inflammatory responses.
