Phulara Nav Raj, Rege Apurv, Bieberich Charles J, Seneviratne Herana Kamal
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, Maryland 21250, United States.
Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250, United States.
ACS Pharmacol Transl Sci. 2024 Jul 9;7(8):2379-2390. doi: 10.1021/acsptsci.4c00228. eCollection 2024 Aug 9.
Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.
依非韦伦（EFV）是一种常用于治疗人类免疫缺陷病毒感染的药物，已知其会对大脑产生不良反应。虽然已知EFV与血浆脂质水平异常有关，但EFV治疗后脑组织中单个脂质分子的空间定位变化尚待探索。在本研究中，我们采用基质辅助激光解吸/电离质谱成像方法来确定EFV治疗后小鼠大脑中特定区域的脂质变化。我们在小鼠大脑中检测到磷脂酰胆碱（PC）、鞘磷脂（SM）、神经酰胺磷酸肌醇（PI-Cer）和己糖神经酰胺（HexCer）分子独特的空间定位模式。有趣的是，PC(32:0)、PC(38:5)和SM(36:1;O2)在海马区显示出高丰度，而PI-Cer(38:8)在接受EFV治疗的小鼠大脑海马区显示出低丰度。此外，我们观察到在接受EFV治疗的小鼠大脑丘脑区，PC(38:6)、PC(40:6)和PI-Cer(40:3)的丰度较低。此外，与对照组相比，SM(40:1;O2)、SM(42:2;O2)、SM(42:1;O2)、SM(43:2;O2)和SM(43:1;O2)在接受EFV治疗的小鼠大脑胼胝体区积累。然而，HexCer(42:1;O3)在胼胝体区因EFV治疗而减少。为了表征包括脂质代谢酶在内的蛋白质在EFV治疗后的表达模式，我们利用了基于质谱的蛋白质组学方法。从中发现，12种脑蛋白的表达水平在EFV治疗后显著降低。综上所述，这些多组学数据为EFV对脑脂质代谢的影响提供了重要见解。
