{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:45:30Z","timestamp":1788371130287,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T00:00:00Z","timestamp":1730419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["23TPA1068534"],"award-info":[{"award-number":["23TPA1068534"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["R01NS131122"],"award-info":[{"award-number":["R01NS131122"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Transformational Project Award","doi-asserted-by":"publisher","award":["R01NS136154"],"award-info":[{"award-number":["R01NS136154"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["23TPA1068534"],"award-info":[{"award-number":["23TPA1068534"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS131122"],"award-info":[{"award-number":["R01NS131122"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS136154"],"award-info":[{"award-number":["R01NS136154"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u20137 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.<\/jats:p>","DOI":"10.3390\/ijms252111765","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T09:49:14Z","timestamp":1730454554000},"page":"11765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sex and Age-Dependent Effects of miR-15a\/16-1 Antagomir on Ischemic Stroke Outcomes"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7183-9237","authenticated-orcid":false,"given":"Xinlei","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-2261","authenticated-orcid":false,"given":"Shun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"},{"name":"Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"},{"name":"Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4090-7187","authenticated-orcid":false,"given":"Andrew","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqing","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"},{"name":"Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7169-3858","authenticated-orcid":false,"given":"Ke-Jie","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"},{"name":"Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S1474-4422(24)00369-7","article-title":"Global, Regional, and National Burden of Stroke and Its Risk Factors, 1990\u20132021: A Systematic Analysis for the Global Burden of Disease Study 2021","volume":"23","author":"Feigin","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.neuron.2015.05.041","article-title":"Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments","volume":"87","author":"George","year":"2015","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0140-6736(20)31179-X","article-title":"Stroke","volume":"396","author":"Campbell","year":"2020","journal-title":"Lancet"},{"key":"ref_4","first-page":"3238165","article-title":"Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life","volume":"2018","author":"Donkor","year":"2018","journal-title":"Stroke Res. 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