Lipidomics Analysis Reveals a Protective Effect of Myriocin on Cerebral Ischemia/Reperfusion Model Rats

Ceramide accumulation has been associated with ischemic stroke. Myriocin is an effective serine palmitoyltransferase (SPT) inhibitor that reduces ceramide levels by inhibiting the de novo synthesis pathway. However, the role of myriocin in cerebral ischemia/reperfusion (I/R) injury and its underlying mechanism remain unknown. The present study established an experimental rat model of middle cerebral artery occlusion (MCAO). We employed ultra-performance liquid chromatograph quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)–based lipidomic analysis to identify the disordered lipid metabolites and the effects of myriocin in cerebral cortical tissues of rats. In this study, we found 15 characterized lipid metabolites involved in sphingolipid and glycerophospholipid metabolism in cerebral I/R-injured rats, and these alterations were significantly alleviated by myriocin. Specifically, the mRNA expression of metabolism-related enzyme genes was detected by real-time quantitative polymerase chain reaction (RT-qPCR). We demonstrated that myriocin could regulate the mRNA expression of ASMase, NSMase, SGMS1, SGMS2, ASAH1, ACER2, and ACER3, which are involved in sphingolipid metabolism and PLA2, which is involved in glycerophospholipid metabolism. Moreover, TUNEL and Western blot assays showed that myriocin plays a key role in regulating neuronal cell apoptosis. In summary, the present work provides a new perspective for the systematic study of metabolic changes in ischemic stroke and the therapeutic applications of myriocin.