Journal
NEUROPSYCHIATRIC DISEASE AND TREATMENT
Volume 17, Issue -, Pages 1989-2002Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/NDT.S290237
Keywords
ischemia/reperfusion injury; I/R; miR-9-3p; FGF19; GSK-3 beta; Nrf2
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The study reveals that inhibition of miR-9-3p protects against cerebral ischemia/reperfusion injury by targeting FGF19 and activating GSK-3 beta/Nrf2/ARE signaling-mediated antioxidant responses. Downregulation of miR-9-3p attenuates infarct volume and neurological outcomes, while overexpression exacerbates the damage, indicating a potential therapeutic target for ischemic stroke.
Purpose: MicroRNAs (miRNAs) are emerging as essential regulators in the development of cerebral ischemia/reperfusion (I/R) injury. This study aimed to explore the regulation of miR-9-3p on FGF19-GSK-3 beta/Nrf2/ARE signaling in cerebral I/R injury. Materials and Methods: A mouse model with I/R injury was constructed by middle cerebral artery occlusion (MCAO) and an HT22 cell model was established by oxygen-glucose deprivation/reperfusion (OGD/R). The expression of miR-9-3p was detected by RT-qPCR. Protein expression of fibroblast growth factor 19 (FGF19), cleaved caspase-3, and GSK-3 beta signaling-related proteins (p-GSK-3 beta and Nrf2) were detected by Western blot. Cell viability was assessed by MTT assay. Oxidative stress was detected by commercial kits. The target of miR-9-3p was predicted by TargetScan and confirmed by luciferase reporter assay. The effects of miR-9-3p on GSK-3 beta/Nrf2/ARE signaling were assessed by rescue experiments. Results: MiR-9-3p was significantly upregulated in brain tissues of MCAO/R-treated mice and OGD/R-treated HT22 cells. Downregulation of miR-9-3p attenuated infarct volume and neurological outcomes of MCAO/R-treated mice in vivo and OGD/R-induced cell injury and oxidative stress in vitro, while overexpression of miR-9-3p showed the opposite effects. MiR-9-3p directly bound to the 3'-untranslated region of FGF19 and negatively regulated its expression. Inhibition of miR-9-3p enhanced GSK-3 beta/Nrf2/ARE signaling-mediated antioxidant response, while this effect was partially eliminated by FGF19 or Nrf2 silencing. Conclusion: Our study suggests that inhibition of miR-9-3p protects against cerebral I/R injury through activating GSK-3 beta/Nrf2/ARE signaling-mediated antioxidant responses by targeting FGF19, providing a potential therapeutic target for ischemic stroke.
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