Acute hypoxic-ischemic brain damage (HIBD) mainly occurs in adults as a result of perioperative cardiac arrest and asphyxia. The benefits of n-3 polyunsaturated fatty acids (n-3 PUFAs) in maintaining brain growth and development are well documented. However, possible protective targets and underlying mechanisms of mfat-1 mice on HIBD require further investigation. The mfat-1 transgenic mice exhibited protective effects on HIBD, as indicated by reduced infarct range and improved neurobehavioral defects. RNA-seq analysis showed that multiple pathways and targets were involved in this process, with the anti-inflammatory pathway as the most significant. This study has shown for the first time that mfat-1 has protective effects on HIBD in mice. Activation of a G protein-coupled receptor 120 (GPR120)-related anti-inflammatory pathway may be associated with perioperative and postoperative complications, thus innovating clinical intervention strategy may potentially benefit patients with HIBD.
BackgroundAcute hypoxic-ischemic brain damage (HIBD) occurs not only in newborns but also in adults. It is associated with series of cellular and biochemical pathways that lead to neuronal injury. N-3 polyunsaturated fatty acids (PUFAs) have been reported to improve neuron functions via G protein-coupled receptor 120 signal pathway in cells or with exogenous supplementation. Possible protective targets and underlying mechanisms of high proportion of n-3/n-6 PUFAs contained in the brains of mfat-1 transgenic mice on HIBD-induced adult brain damage needed to be further investigated.MethodsThe adult C57BL/6J (WT) and mfat-1 transgenic mice adopted HIBD model. A gas chromatograph was used to determine the composition of PUFAs. Neurological deficit scores test, TTC staining and Nissl staining were employed to evaluate the neuroprotective effects. Cleaved-caspase3 and TUNEL experiment were used to detect apoptosis after injury. Inflammatory factors were detected by ELISA assay. RNA-sequencing analysis was processed and the differential expressed genes were verified by real-time quantitative PCR. Key factors related to inflammation were detected by immunofluorescence and western blot.ResultsThe mfat-1 transgenic mice with high ratio of n-3/n-6 PUFAs in brain tissues were showed to have protective effects on HIBD-induced brain damage by reduced infarct range and greatly improved neurobehavioral defects. Further analysis revealed that the level of neuronal necrosis, apoptosis and inflammation induced by brain injury were relatively low. RNA-seq analysis showed multiple pathways and targets involved in this process. Significant activation of GPR120, reduction of phosphorylation of TAK1 and NF-κB P65 in the downstream of the pro-inflammatory pathway were found in the brains of mfat-1 mice on HIBD. ConclusionsThe study showed that mfat-1 transgenic mice had protective effects on HIBD-induced brain injury by multiple pathways. Activation of GPR120 and reduction of related pro-inflammatory pathway involved in this process, which may improve or prevent dangerous perioperative and postoperative complications, innovate clinical intervention strategy and potentially benefit more patients.
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