Cited by 217MicroRNA in disease regulationNeuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke Management

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An Antagomir to MicroRNA Let7f Promotes Neuroprotection in an Ischemic Stroke Model

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Selvamani, Amutha, Sathyan, Pratheesh, Miranda, Rajesh C., Sohrabji, Farida·2012·PLoS ONE

DOI 10.1371/journal.pone.0032662PMC PMC3290559

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Abstract

We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothesized that microRNAs (miRNAs) that target the IGF-1 signaling family for translation repression could be alternatively suppressed to promote IGF-1-like neuroprotection. Here, we report that two conserved IGF pathway regulatory microRNAs, Let7f and miR1, can be inhibited to mimic and even extend the neuroprotection afforded by IGF-1. Anti-mir1 treatment, as late as 4 hours following ischemia, significantly reduced cortical infarct volume in adult female rats, while anti-Let7 robustly reduced both cortical and striatal infarcts, and preserved sensorimotor function and interhemispheric neural integration. No neuroprotection was observed in animals treated with a brain specific miRNA unrelated to IGF-1 (anti-miR124). Remarkably, anti-Let7f was only effective in intact females but not males or ovariectomized females indicating that the gonadal steroid environment critically modifies miRNA action. Let7f is preferentially expressed in microglia in the ischemic hemisphere and confirmed in ex vivo cultures of microglia obtained from the cortex. While IGF-1 was undetectable in microglia harvested from the non-ischemic hemisphere, IGF-1 was expressed by microglia obtained from the ischemic cortex and was further elevated by anti-Let7f treatment. Collectively these data support a novel miRNA-based therapeutic strategy for neuroprotection following stroke.

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See all 217

Authors: Selvamani, A., Sathyan, P., Miranda, R. C., & Sohrabji, F.
Affiliations: Texas A&M Health Science Center (US)
Corresponding author: Sohrabji, Farida
ORCID: Selvamani, Amutha
Miranda, Rajesh C.
Sohrabji, Farida
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2012-02-29
Volume: 7
Issue: 2
Pages: e32662
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0032662
PMC: PMC3290559
OpenAlex: W2071432376
Cited by: 217
References: 79
Citations by year: 2026: 1 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 12 · 2020: 16 · 2019: 19 · 2018: 18 · 2017: 26 · 2016: 20 · 2015: 23 · 2014: 27 · 2013: 22 · 2012: 4
FWCI: 8.02
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
OakTrust (Texas A&M University Libraries) (submittedVersion)
Funders: National Institutes of Health
National Institute on Aging (R01AG027684, AG027684, AG028303, R01AG028303)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
Keywords: ischemic stroke, neuroprotection, microRNA, let-7f, miR-1, insulin-like growth factor I, IGF-1 signaling, microglia, sex differences, infarct size, sensorimotor function, hemispheric integration, sex steroids
MeSH terms: Animals, Behavior, Animal, Disease Models, Animal, Female, Gene Expression Regulation, Insulin-Like Growth Factor I, Ischemia, Male, Sex Factors, Reperfusion Injury, Microglia, Neuroprotective Agents, Stroke, MicroRNAs, Rats

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An Antagomir to MicroRNA Let7f Promotes Neuroprotection in an Ischemic Stroke Model

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