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MiR-182 Inhibition Protects Against Experimental Stroke in vivo and Mitigates Astrocyte Injury and Inflammation in vitro via Modulation of Cortactin Activity

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Abstract

Ischemic stroke remains a devastating cerebrovascular disease that accounts for a high proportion of mortality and disability worldwide. MicroRNAs (miRNAs) are a class of small non-coding RNAs that are responsible for regulation of post-transcriptional gene expression, and growing evidence supports a role for miRNAs in stroke injury and recovery. The current study examined the role of miR-182 in experimental stroke using both in vitro and in vivo models of ischemic injury. Brain levels of miR-182 significantly increased after transient middle cerebral artery occlusion (MCAO) in mice and in primary astrocyte cultures subjected to combined oxygen–glucose deprivation/reperfusion (OGD/R) injury. In vivo, stroke volume and neurological score were significantly improved by pre-treatment with miR-182 antagomir. Astrocyte cultures stressed with OGD/R resulted in mitochondrial fragmentation and downregulation of cortactin, an actin-binding protein. Inhibition of miR-182 significantly preserved cortactin expression, reduced mitochondrial fragmentation and improved astrocyte survival after OGD/R. In parallel, lipopolysaccharide (LPS)-induced nitric-oxide release in astrocyte cultures was significantly reduced by miR-182 inhibition, translating to reduced injury in primary neuronal cultures subjected to conditioned medium from LPS-treated astrocytes. These findings identify miR-182 and/or cortactin as potential clinical targets to preserve mitochondrial structure and mitigate neuroinflammation and cell death after ischemic stroke.

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Data Availability

All data from this study are available for review upon request.

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Funding

American Heart Association Grant #14FTF19970029 and NIH Grant #NS119462 to CS.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305-5117, USA

    Qasim M. Alhadidi, Lijun Xu, Xiaoyun Sun & Creed M. Stary

  2. Department of Pharmacy, Al-Yarmok University College, Diyala, Iraq

    Qasim M. Alhadidi

  3. Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, Saudi Arabia

    Yusuf S. Althobaiti

  4. Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Taif, Saudi Arabia

    Yusuf S. Althobaiti, Atiah Almalki & Hashem O. Alsaab

  5. Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia

    Atiah Almalki

  6. Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif, Saudi Arabia

    Hashem O. Alsaab

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  1. Qasim M. Alhadidi
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  2. Lijun Xu
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Correspondence to Creed M. Stary.

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Alhadidi, Q.M., Xu, L., Sun, X. et al. MiR-182 Inhibition Protects Against Experimental Stroke in vivo and Mitigates Astrocyte Injury and Inflammation in vitro via Modulation of Cortactin Activity. Neurochem Res 47, 3682–3696 (2022). https://doi.org/10.1007/s11064-022-03718-6

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  • DOI: https://doi.org/10.1007/s11064-022-03718-6

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