Sex and Age-Dependent Effects of miR-15a/16-1 Antagomir on Ischemic Stroke Outcomes
Xinlei Huang1, Shun Li1,2, Na Qiu1,2
1Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Abstract:
Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3-7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies.
Insights
Inhibiting microRNA-15a/16-1 (miR-15a/16-1) with antagomirs improved outcomes after ischemic stroke in mice, particularly in younger animals. This suggests a potential new therapy for stroke, considering sex and age differences.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Ischemic stroke is a major global health concern, leading to significant disability and mortality.
- MicroRNAs (miRs), including miR-15a/16-1, are increasingly recognized for their role in stroke pathophysiology, with upregulation potentially worsening ischemic damage.
- Sex and age are known to influence stroke outcomes, highlighting the need to investigate age- and sex-dependent therapeutic effects.
Purpose of the Study:
- To investigate if inhibiting miR-15a/16-1 with antagomirs can mitigate cerebral ischemia/reperfusion (I/R) injury.
- To determine if the therapeutic effects of miR-15a/16-1 inhibition are dependent on sex and age.
Main Methods:
- A transient middle cerebral artery occlusion (tMCAO) model was used in young (3 months) and aged (18 months) male and female C57/BL mice.
- Mice received either a miR-15a/16-1 antagomir or a control antagomir (NC) intravenously 2 hours post-occlusion.
- Neurobehavioral function and infarct volumes were assessed at 3 and 7 days post-reperfusion.
Main Results:
- Treatment with the miR-15a/16-1 antagomir significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7.
- These beneficial effects were more pronounced in young mice compared to aged mice.
- Young female mice demonstrated superior survival and sensorimotor function compared to young male mice, suggesting a sex-dependent effect.
Conclusions:
- Inhibition of miR-15a/16-1 using antagomirs represents a promising therapeutic strategy for ischemic stroke.
- The therapeutic efficacy of miR-15a/16-1 antagomirs is influenced by both age and sex, with younger females showing the most benefit.
- Future therapeutic strategies for ischemic stroke should consider the interplay of miR-15a/16-1, estradiol, and age- and sex-specific biological pathways.
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01:15Ischemic Stroke ll: Pathophysiology