Downregulation of microRNA-196a attenuates ischemic brain injury in rats by directly targeting HMGA1

OBJECTIVE: Dysfunction of the microRNA (miRNA) network is a major regulator in neurological diseases. However, little is known about the functional significance of miRs in ischemic brain injury. This study was designed to investigate the functional behaviors and regulatory mechanisms of miR-196a in ischemic brain injury.

MATERIALS AND METHODS: Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. The expression levels of miR-196a and HMGA1 were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), Western blotting, and/or immunocytochemistry. The role of miR-196a in cerebral infarction and brain cell apoptosis was determined by infarct volume estimation and Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay, respectively. Bioinformatics software and Luciferase analysis were used to predict and confirm the targets of miR-196a.

RESULTS: The results showed that the miR-196a expression was significantly increased in rat brain after MCAO and in cultured neonatal rat cortical neurons after oxygen-glucose deprivation (OGD). Pretreatment with antagomiR-196a by intracerebroventricular markedly reduced the miR-196a mRNA and HMGA1 protein of the brain in rats subjected to MCAO. Notably, the knockdown of miR-196a could protect MCAO rats against cerebral infarction and brain cell apoptosis. In the OGD model, apoptosis and miR-196a expressions were inhibited, while High-Mobility-Group-A1 (HMGA1) levels were increased in cortical neurons in a time-dependent manner. Moreover, HMGA1 was the target gene of miR-196a. MiR-196a overexpression promoted OGD-induced cortical neurons apoptosis possibly through negative regulation of HMGA1.

CONCLUSIONS: These findings indicated a crucial role of miR-196a in regulating infarct volume and neuronal cell death under cerebral ischemia, thus offering a new target for the development of therapeutic agents against ischemic brain injury.

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