Abstract
Hypoxia–ischaemia (HI) remains a major cause of foetal brain damage presented a scarcity of effective therapeutic approaches. Dexmedetomidine (DEX) and microRNA‐140‐5p (miR‐140‐5p) have been highlighted due to its potentially significant role in the treatment of cerebral ischaemia. This study was to investigate the role by which miR‐140‐5p provides cerebral protection using DEX to treat hypoxic–ischaemic brain damage (HIBD) in neonatal rats via the Wnt/β‐catenin signalling pathway. The HIBD rat models were established and allocated into various groups with different treatment plans, and eight SD rats into sham group. The learning and memory ability of the rats was assessed. Apoptosis and pathological changes in the hippocampus CA1 region and expressions of the related genes of the Wnt/β‐catenin signalling pathway as well as the genes responsible of apoptosis were detected. Compared with the sham group, the parameters of weight, length growth, weight ratio between hemispheres, the rate of reaching standard, as well as Bcl‐2 expressions, were all increased. Furthermore, observations of increased levels of cerebral infarction volume, total mortality rate, response times, total response duration, expressions of Wnt1, β‐catenin, TCF‐4, E‐cadherin, apoptosis rate of neurons, and Bax expression were elevated. Following DEX treatment, the symptoms exhibited by HIBD rats were ameliorated. miR‐140‐5p and si‐Wnt1 were noted to attenuate the progression of HIBD. Our study demonstrates that miR‐140‐5p promotes the cerebral protective effects of DEX against HIBD in neonatal rats by targeting the Wnt1 gene through via the negative regulation of the Wnt/β‐catenin signalling pathway.
Highlights
Hypoxic–ischaemic brain damage (HIBD) represents a commonly occurring life-threatening disorder in the neonatal period, which is observed in patients with stroke or cardiac arrest.[1, 2] HIBD leads to permanent brain damage in infants and is frequently accompanied by various disabilities, such as cerebral palsy (10% infants), cognitive disorders (25%-50% infants), learning disabilities and epilepsy.[3, 4] HIBD, caused either in part or by total cerebral hypoxia, cerebral blood flow reduction and suspensions, is widely regarded as a key factor in central nervous system diseases.[5]
A rat model of HIBD was successfully established according to the prescribed method in our procedure, which demonstrated that the neuroprotective effect in treating HIBD could be achieved via placenta-derived mesenchymal stem cells through relieving oxidative stress.[3]
GPR177 has been demonstrated as being a Wnt transcriptional target essential for the secretion of Wnt, allowing miR-140-5p to target Wnt1.21–23 Previous reports have indicated that Fzd[6], which is generally regarded to be a receptor in the Wnt pathway as belonging to a negative regulator of the Wnt/ b-catenin signalling pathway, suggesting miR-140-5p could target the Wnt gene and regulate the Wnt/b-catenin signalling pathway negatively.[24]
Summary
Hypoxic–ischaemic brain damage (HIBD) represents a commonly occurring life-threatening disorder in the neonatal period, which is observed in patients with stroke or cardiac arrest.[1, 2] HIBD leads to permanent brain damage in infants and is frequently accompanied by various disabilities, such as cerebral palsy (10% infants), cognitive disorders (25%-50% infants), learning disabilities and epilepsy.[3, 4] HIBD, caused either in part or by total cerebral hypoxia, cerebral blood flow reduction and suspensions, is widely regarded as a key factor in central nervous system diseases.[5]. Studies have revealed miR-1405p plays an essential angiogenesis role in the ischaemia model via its regulation of VEGFA, which may be beneficial for cerebral ischaemia treatment.[8] The combination of miRNAs reduction and Wnt/b-catenin signalling pathway could promote cancer metastasis, carcinogenesis and even drug resistance.[11] Reports have indicated that the mechanism of cell apoptosis is involved in the pathogenesis of nerve injury following the occurrence of hypoxia–ischaemia, suggesting that antiapoptotic actions could reverse neuronal damage.[12, 13] The Wnt/bcatenin signalling pathway plays a central role in hypoxia–ischaemia (HI) as well as in other neurodegenerative disorders, revealing a potential target for the treatment of HIBD.[14] Dexmedetomidine (DEX) has been reported to up-regulate the blood pressure and heart rate, as well as down-regulating HIBD.[15] the central aim of our study was to explore the effect of miR-140-5p by targeting Wnt[1] through the Wnt/b-catenin signalling pathway in relation to the cerebral protection role of DEX from HIBD in neonatal rats
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