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Up-Regulation of MiR-9-5p Inhibits Hypoxia-Ischemia Brain Damage Through the DDIT4-Mediated Autophagy Pathways in Neonatal Mice

Overview
Specialty Pharmacology
Date 2023 Apr 28
PMID 37113470
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Abstract

Introduction: Hypoxia-ischemia (HI) remains the leading cause of cerebral palsy and long-term neurological sequelae in infants. Despite intensive research and many therapeutic approaches, there are limited neuroprotective strategies against HI insults. Herein, we reported that HI insult significantly down-regulated microRNA-9-5p (miR-9-5p) level in the ipsilateral cortex of neonatal mice.

Methods: The biological function and expression patterns of protein in the ischemic hemispheres were evaluated by qRT-PCR, Western Blotting analysis, Immunofluorescence and Immunohistochemistry. Open field test and Y-maze test were applied to detect locomotor activity and exploratory behavior and working memory.

Results: Overexpression of miR-9-5p effectively alleviated brain injury and improved neurological behaviors following HI insult, accompanying with suppressed neuroinflammation and apoptosis. MiR-9-5p directly bound to the 3' untranslated region of DNA damage-inducible transcript 4 (DDIT4) and negatively regulated its expression. Furthermore, miR-9-5p mimics treatment down-regulated light chain 3 II/light chain 3 I (LC3 II/LC3 I) ratio and Beclin-1 expression and decreased LC3B accumulation in the ipsilateral cortex. Further analysis showed that DDIT4 knockdown conspicuously inhibited the HI-up-regulated LC3 II/ LC3 I ratio and Beclin-1 expression, associating with attenuated brain damage.

Conclusion: The study indicates that miR-9-5p-mediated HI injury is regulated by DDIT4-mediated autophagy pathway and up-regulation of miR-9-5p level may provide a potential therapeutic effect on HI brain damage.

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Zhu L, Ma L, Du X, Jiang Y, Gao J, Fan Z Mol Neurobiol. 2024; 61(10):7845-7861.

PMID: 38433165 PMC: 11415474. DOI: 10.1007/s12035-024-04075-x.

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