Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, Henan Province, People's Republic of China.
J Mol Neurosci. 2022 Sep;72(9):1846-1858. doi: 10.1007/s12031-022-02014-w. Epub 2022 Jul 1.
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.
神经酰胺积累与缺血性中风有关。长川霉素是一种有效的丝氨酸棕榈酰转移酶（SPT）抑制剂，通过抑制从头合成途径降低神经酰胺水平。然而，长川霉素在脑缺血/再灌注（I/R）损伤中的作用及其潜在机制尚不清楚。本研究建立了大脑中动脉闭塞（MCAO）的实验大鼠模型。我们采用超高效液相色谱四极杆飞行时间质谱（UPLC-Q-TOF/MS）-基于脂质组学分析来鉴定受干扰的脂质代谢物以及长川霉素对大鼠大脑皮质组织的影响。在这项研究中，我们发现了 15 种与脑 I/R 损伤大鼠鞘脂和甘油磷脂代谢相关的特征脂质代谢物，这些变化被长川霉素明显缓解。具体而言，通过实时定量聚合酶链反应（RT-qPCR）检测代谢相关酶基因的 mRNA 表达。我们表明，长川霉素可以调节鞘脂代谢相关的 ASMase、NSMase、SGMS1、SGMS2、ASAH1、ACER2 和 ACER3 以及甘油磷脂代谢相关的 PLA2 的 mRNA 表达。此外，TUNEL 和 Western blot 检测表明，长川霉素在调节神经元细胞凋亡中起关键作用。总之，本工作为缺血性中风代谢变化的系统研究和长川霉素的治疗应用提供了新的视角。
