RESUMO
Dexmedetomidine (Dex) possesses analgesic and anaesthetic values and reported being used in cerebral ischaemic injury therapeutics. Accumulating studies have determined the effect of microRNAs (miRNAs) on the cerebral ischaemic injury. Thus, the present study aimed to unravel the molecular mechanism of miR-381 and Dex in cerebral ischaemic injury. For this purpose, the cerebral ischaemic injury rat model was established by induction of middle cerebral artery occlusion (MCAO) and expression of miR-381 and IRF4 was determined. Thereafter, MCAO rats were treated with Dex, miR-381 mimic, miR-381 inhibitor and oe-IRF4 respectively, followed by evaluation of neurological function. Furthermore, neuron cells were isolated from the hippocampus of rats and subjected to oxygen-glucose deprivation (OGD). Then, OGD-treated neuron cells and primary neuron cells were examined by gain- and loss-of-function assay. Neuron cell apoptosis was detected using TUNEL staining and flow cytometry. The correlation between interferon regulatory factor 4 (IRF4) and interleukin (IL)-9 was detected. Our results showed down-regulated miR-38 and up-regulated IRF4 in MCAO rats. Besides, IRF4 was targeted by miR-381 in neuron cells. Dex and overexpressed miR-381, or silenced IRF4 improved the neurological function and inhibited neuron cell apoptosis in MCAO rats. Additionally, in MCAO rats, Dex was found to increase the miR-381 expression and reduced IRF4 expression to decrease the IL-9 expression, which suppressed the inflammatory response and cell apoptosis both in vivo and in vitro. Importantly, our study demonstrated that Dex elevated the expression of miR-381, which ultimately results in the inhibition of inflammation response in rats with cerebral ischaemic injury.
Assuntos
Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Dexmedetomidina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Reguladores de Interferon/metabolismo , MicroRNAs/genética , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Glucose/metabolismo , Fatores Reguladores de Interferon/genética , Interleucina-9/genética , Interleucina-9/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxigênio/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Hypoxic-ischemic brain damage (HIBD) is a common neurological disorder. Emerging reports reveal that long non-coding RNAs and microRNAs (miRs) are implicated in the progress of HIBD. In this study we tried to ascertain whether lncRNA MALAT1, with the involvement of miR-429 and WNT1, affects HIBD. Initially, a HIBD mouse model was established. Then, we treated HIBD mice with dexmedetomidine (DEX) and then up- or down-regulated the expression of MALAT1, miR-429 and WNT1 in HIBD mice and neurons. Meanwhile, brain injury and hippocampal neuronal apoptosis were evaluated. Moreover, the interaction among MALAT1, miR-429 and WNT1 in HIBD was investigated. MALAT1 and WNT1 were high-expressed in brain tissues of HIBD mice while miR-429 was low-expressed in brain tissues from HIBD mice. Interestingly, MALAT1 silencing was observed to enhance the cerebral protection of DEX against HIBD. In addition, it was confirmed that MALAT1 sponged miR-429 downregulating expression of miR-429, thereby promoting apoptosis of hippocampal neurons. This effect was achieved through up-regulating the level of WNT1. Taken together, this study demonstrates that silencing of MALAT1 enhances the cerebral protection of DEX against HIBD by suppressing WNT1 expression through miR-429.