Inhibition of miR-141-3p Ameliorates the Negative Effects of Poststroke Social Isolation in Aged Mice

While good this seems way too premature since it still requires human followup testing. Are your doctor and stroke hospital being responsible and doing any followup to get research going?

Or will NOTHING BE DONE since everyone in stroke is

waiting for SOMEONE ELSE TO SOLVE THE PROBLEM?

Or you could get them 100% recovered and you wouldn't have to solve this secondary problem. Why isn't 100% recovery the main goal for stroke researchers? TOO HARD?

Congratulations to Rajkumar Verma,1st prize recipient of the 2018 #Stroke Progress and Innovation Award! 

Inhibition of miR-141-3p Ameliorates the Negative Effects of Poststroke Social Isolation in Aged Mice

 

Rajkumar Verma

,

Rodney M. Ritzel

,

Nia M. Harris

,

Juneyoung Lee

,

TaeHee Kim

,

Gopal Pandi

,

Raghu Vemuganti

and

Louise D. McCullough

Originally published30 Jul 2018https://doi.org/10.1161/STROKEAHA.118.020627Stroke. 2018;49:1701–1707

Abstract

Background and Purpose—

Social isolation increases mortality and impairs recovery after stroke in clinical populations. These detrimental effects have been recapitulated in animal models, although the exact mechanism mediating these effects remains unclear. Dysregulation of microRNAs (miRNAs) occurs in both strokes as well as after social isolation, which trigger changes in many downstream genes. We hypothesized that miRNA regulation is involved in the detrimental effects of poststroke social isolation in aged animals.

Methods—

We pair-housed 18-month-old C57BL/6 male mice for 2 weeks before a 60-minute right middle cerebral artery occlusion or sham surgery and then randomly assigned mice to isolation or continued pair housing immediately after surgery. We euthanized mice either at 3, 7, or 15 days after surgery and isolated the perilesional frontal cortex for whole microRNAome analysis. In an additional cohort, we treated mice 1 day after stroke onset with an in vivo-ready antagomiR-141 for 3 days.

Results—

Using whole microRNAome analysis of 752 miRNAs, we identified miR-141-3p as a unique miRNA that was significantly upregulated in isolated mice in a time-dependent manner up to 2 weeks after stroke. Posttreatment with an antagomiR-141-3p reduced the postisolation-induced increase in miR-141-3p to levels almost equal to those of pair-housed stroke controls. This treatment significantly reduced mortality (by 21%) and normalized infarct volume and neurological scores in poststroke-isolated mice. Quantitative PCR analysis revealed a significant upregulation of Tgfβr1 (transforming growth factor beta receptor 1, a direct target of miR-141-3p) and Igf-1 (insulin-like growth factor 1) mRNA after treatment with antagomiR. Treatment also increased the expression of other pleiotropic cytokines such as Il-6 (interleukin 6) and Tnf-α (tumor necrosis factor-α), an indirect or secondary target) in brain tissue.

Conclusions—

miR-141-3p is increased with poststroke isolation. Inhibition of miR-141-3p improved mortality, neurological deficits, and decreased infarct volumes. Importantly, these therapeutic effects occurred in aged animals, the population most at risk for stroke and poststroke isolation.

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Introduction

Emerging evidence from experimental and clinical studies suggests that social isolation (SI) is not only a risk factor for a stroke but also contributes to increased stroke severity and delayed functional recovery.^1–3 Exacerbation of inflammation and a reduction in prosurvival growth factors mediate the detrimental effects of poststroke SI.^3–5 Social interaction can overcome these negative effects by promoting adaptive behaviors and favorable neuroendocrine responses to biological stressors.⁶ SI is particularly relevant to the elderly as this population has a high risk of both strokes and isolation.^3,7 We have previously found that aged mice that were socially isolated after stroke do not recover completely and exhibit continued deficits in memory/motor function and elevation in inflammation even months after ischemic injury.³ Given the complex pathophysiology and additional contribution of aging and SI, there is a critical need to concurrently target multiple effector pathways involved in stroke pathology.
MicroRNAs (miRNAs) are a class of small endogenously expressed noncoding RNAs that regulate gene transcription and translation to orchestrate mRNA and protein expression.⁸ The role of miRNAs in stroke has been a subject of increasing interest because the first miRNA expression profiling study in cerebral ischemia was performed in 2008.⁹ Poststroke recovery affects several miRNAs including miR-129, miR-141, miR-181a-d, and miR-200c, and treatment with mimics or antagomiRs of these miRNAs reduce injury and improve chronic behavioral recovery in young mice.¹⁰ Similar studies are lacking in aged animals. miRNAs also mediate many aspects of social interaction. Social environments can directly influence miRNA expression, which then triggers expression of a plethora of downstream genes. For example, miR-124-5p is involved in social and behavioral deficits in frontotemporal dementia,¹¹ miR-200c in major depressive disorder,¹² and miR-181c-5p in the social withdrawal associated with autism.¹³
Poststroke inflammation plays a critical role in stroke injury and recovery, which is mainly initiated by rapid activation of microglia.^5,14,15 Advanced age and SI enhance microglia-mediated inflammation either by disturbing the homeostatic balance between proinflammatory and anti-inflammatory/reparative cytokine secretion and by reducing its scavenger functions (eg, phagocytosis), contributing to poststroke pathophysiology.¹⁶ Interestingly, several miRNAs play critical regulatory roles in microglial activation and function.¹⁷ This led us to hypothesize that targeted manipulation of miRNAs, which concurrently regulate multiple effector pathways, prevent the detrimental effect of poststroke SI on stroke recovery by altering the microglial response.