School of Pharmacy, College of Medicine , National Taiwan University , Taipei 100 , Taiwan.
The Metabolomics Core Laboratory, Center of Genomic Medicine , National Taiwan University , Taipei 100 , Taiwan.
J Proteome Res. 2019 Sep 6;18(9):3470-3478. doi: 10.1021/acs.jproteome.9b00370. Epub 2019 Jul 30.
Sphingolipids (SPLs) have been proposed as potential therapeutic targets for strokes, but no reports have ever profiled the changes of the entire range of SPLs after a stroke. This study applied sphingolipidomic methods to investigate the temporal and individual changes in the sphingolipidome including the effect of atorvastatin after ischemic brain injury. We conducted sphingolipidomic profiling of mouse brain tissue by liquid chromatography-electrospray ionization tandem mass spectrometry at 3 h and 24 h after 1 h of middle cerebral artery occlusion (MCAO), and SPL levels were compared with those of the control group. At 3 h post-MCAO, ceramides (Cers) exhibited an increase in levels of long-chain Cers but a decrease in very-long-chain Cers. Moreover, sphingosine, the precursor of sphingosine-1-phosphate (S1P), decreased and S1P increased at 3 h after MCAO. In contrast to 3 h, both long-chain and very-long-chain Cers showed an increased trend at 24 h post-MCAO. Most important, the administration of atorvastatin improved the neurological function of the mice and significantly reversed the SPL changes resulting from the ischemic injury. Furthermore, we used plasma samples from nonstroke control and stroke patients at time points of 72 h after a stroke, and found a similar trend of Cers as in the MCAO model. This study successfully elucidated the overall effect of ischemic injury on SPL metabolism with and without atorvastatin treatment. The network of SPL components that change upon ischemic damage may provide novel therapeutic targets for ischemic stroke.
鞘脂类（SPLs）已被提议作为中风的潜在治疗靶点，但尚无报道描述中风后 SPL 整体范围的变化。本研究应用鞘脂组学方法研究了包括缺血性脑损伤后阿托伐他汀作用在内的鞘脂组在时间和个体上的变化。我们通过液相色谱-电喷雾电离串联质谱法对大脑中动脉闭塞（MCAO）后 1 小时的小鼠脑组织进行了鞘脂组学分析，在 3 小时和 24 小时与对照组比较 SPL 水平。在 MCAO 后 3 小时，神经酰胺（Cer）表现出长链 Cer 水平升高而非常长链 Cer 水平降低。此外，在 MCAO 后 3 小时，作为鞘氨醇-1-磷酸（S1P）前体的鞘氨醇减少，而 S1P 增加。与 3 小时相反，长链和非常长链 Cer 在 MCAO 后 24 小时均显示出增加的趋势。最重要的是，阿托伐他汀的给药改善了小鼠的神经功能，并显著逆转了缺血损伤引起的 SPL 变化。此外，我们使用中风后 72 小时的非中风对照和中风患者的血浆样本，发现 Cer 有类似的趋势与 MCAO 模型一致。本研究成功阐明了缺血性损伤对 SPL 代谢的整体影响，以及有无阿托伐他汀治疗的影响。在缺血性损伤下发生变化的 SPL 成分网络可能为缺血性中风提供新的治疗靶点。
