Introduction: MicroRNAs (miRNAs) are a class of short non-coding RNAs that have been identified as a powerful interventional tool for many diseases, including stroke. Very recent studies have found that microRNAs also mediate aspects of social interaction. Social environments can directly influence miRNA expression, which then triggers a plethora of downstream gene changes. Social isolation (SI) impairs stroke recovery and leads to inflammation. We hypothesize that miRNAs are involved in the detrimental effects of post-stroke social isolation.
Methods: Eighteen-month-old male C57BL/6 mice were pair housed (PH) for two weeks prior to stroke and randomly assigned to various housing conditions (ST-ISO or ST-PH) immediately after stroke (ST). Mice were sacrificed either at 3, 7 or 14 days after 60-minute right MCAO or sham surgery (n=4-6/group) and perilesional frontal cortex was isolated for miRNA analysis. Total RNA was isolated using either Qiagen miRNeasy® Mini Kit/ miRVANA miRNA isolation kit (Ambion, Life technologies). Whole miRNOme analysis of total RNA isolated from brain tissue was performed using miRCURY LNATM Universal RT microRNA. Post-treatment with an ‘in vivo ready’ antagomir of miR-141-3p (7mg/kg i.v/day x 3 days; n=4/group) was given through lateral tail veins.
Results: Using whole miRNOme analysis of approx. 800 miRNA, we found miR-141-3p was a unique miRNA whose expression was significantly upregulated in a time dependent manner up to day 14 after stroke. The post treatment with an ‘in vivo ready’ antogomir of miR-141-3p reduced the isolation-induced increase in miR-141-3p to levels almost equal to that of pair-housed controls. Post- treatment significantly reduced mortality (by 21% as compared to -ve control) and sensory motor deficits after stroke. mRNA targets analysis study using qPCR confirmed the significant (p<0.05 vs Neg Control ) upregulation of target several genes like arg-1, ccl22 and TGFbr1, markers of M2 type microglial activation, after antogomir treatment. Summary: The present data suggests the unique role of miR-141-3p in post stroke isolation. Temporal expression profiling studies suggest its validation as a potential targets. Post treatment data confirms the in vivo feasibility of miRNA modulation after stroke.