Kong Ling-Lei, Gao Li, Wang Ke-Xin, Liu Nan-Nan, Liu Cheng-di, Ma Guo-Dong, Yang Hai-Guang, Qin Xue-Mei, Du Guan-Hua
Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China.
Acta Pharmacol Sin. 2021 Aug;42(8):1223-1234. doi: 10.1038/s41401-021-00664-x. Epub 2021 Apr 15.
Hemorrhagic transformation (HT) is a common serious complication of stroke after thrombolysis treatment, which limits the clinical use of tissue plasminogen activator (t-PA). Since early diagnosis and treatment for HT is important to improve the prognosis of stroke patients, it is urgent to discover the potential biomarkers and therapeutic drugs. Recent evidence shows that pinocembrin, a natural flavonoid compound, exerts anti-cerebral ischemia effect and expands the time window of t-PA. In this study, we investigated the effect of pinocembrin on t-PA-induced HT and the potential biomarkers for HT after t-PA thrombolysis, thereby improving the prognosis of stroke. Electrocoagulation-induced thrombotic focal ischemic rats received intravenous infusion of t-PA (10 mg/kg) 6 h after ischemia. Administration of pinocembrin (10 mg/kg, iv) prior t-PA infusion significantly decreased the infarct volume, ameliorated t-PA-induced HT, and protected blood-brain barrier. Metabolomics analysis revealed that 5 differential metabolites in the cerebral cortex and 16 differential metabolites in serum involved in amino acid metabolism and energy metabolism were significantly changed after t-PA thrombolysis, whereas pinocembrin administration exerted significant intervention effects on these metabolites. Linear regression analysis showed that lactic acid was highly correlated to the occurrence of HT. Further experiments confirmed that t-PA treatment significantly increased the content of lactic acid and the activity of lactate dehydrogenase in the cerebral cortex and serum, and the expression of monocarboxylate transporter 1 (MCT 1) in the cerebral cortex; pinocembrin reversed these changes, which was consistent with the result of metabolomics. These results demonstrate that pinocembrin attenuates HT after t-PA thrombolysis, which may be associated with the regulation of endogenous metabolites. Lactic acid may be a potential biomarker for HT prediction and treatment.
出血性转化（HT）是溶栓治疗后中风常见的严重并发症，这限制了组织纤溶酶原激活剂（t-PA）的临床应用。由于对HT进行早期诊断和治疗对于改善中风患者的预后很重要，因此迫切需要发现潜在的生物标志物和治疗药物。最近的证据表明，天然黄酮类化合物白杨素具有抗脑缺血作用，并能延长t-PA的时间窗。在本研究中，我们研究了白杨素对t-PA诱导的HT的影响以及t-PA溶栓后HT的潜在生物标志物，从而改善中风的预后。电凝诱导的血栓性局灶性缺血大鼠在缺血6小时后接受静脉注射t-PA（10mg/kg）。在输注t-PA之前给予白杨素（10mg/kg，静脉注射）可显著降低梗死体积，改善t-PA诱导的HT，并保护血脑屏障。代谢组学分析显示，t-PA溶栓后，大脑皮层中的5种差异代谢物和血清中的16种参与氨基酸代谢和能量代谢的差异代谢物发生了显著变化，而给予白杨素对这些代谢物产生了显著的干预作用。线性回归分析表明，乳酸与HT的发生高度相关。进一步的实验证实，t-PA治疗显著增加了大脑皮层和血清中乳酸的含量以及乳酸脱氢酶的活性，以及大脑皮层中单羧酸转运体1（MCT 1）的表达；白杨素逆转了这些变化，这与代谢组学的结果一致。这些结果表明，白杨素可减轻t-PA溶栓后的HT，这可能与内源性代谢物的调节有关。乳酸可能是预测和治疗HT的潜在生物标志物。
