Pharmacokinetic and metabolomic analyses of the neuroprotective effects of salvianolic acid A in a rat ischemic stroke model
Pharmacokinetic and metabolomic analyses of the neuroprotective effects of salvianolic acid A in a rat ischemic stroke model
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DOI：
10.1038/aps.2017.114
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发表时间：
2017-11-01
影响因子：
8.2
通讯作者：
Wang, Guang-ji
中科院分区：
文献类型：
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作者：
Feng, Si-qi;Nan, A. A.;Wang, Guang-ji
丹酚酸A （SAA）是一种从丹参根中分离得到的水溶性酚酸，具有明显的抗氧化活性和保护脑缺血再灌注（I/R）损伤的作用。然而，SAA能否通过直接靶向脑组织进入中枢神经系统并发挥其保护作用尚不清楚。在本研究中，我们评估了SAA对短暂性大脑中动脉闭塞（tMCAO）后再灌注大鼠的脑保护作用。大鼠在再灌注时分别给予5、10 mg/kg，静脉注射SAA。SAA可显著减少tMCAO大鼠脑梗死面积和脑含水量，减轻神经功能缺损和病理，增强抗炎和抗氧化能力。采用LC-MS/MS检测血浆和脑组织中SAA的浓度。一项药代动力学研究显示，假手术对照组和I/R组大鼠的循环系统SAA暴露量相当，但I/R组大鼠的SAA脑暴露量明显高于假手术对照组（翻倍变化为9.17倍），提示SAA暴露量的增加有助于其脑保护作用。使用基于GC/ ms的代谢组学平台，提取血清和脑组织中的代谢物并进行分析。根据组织数据的代谢组学模式，SAA给药显著调节脑内I/ r引起的代谢紊乱，其程度大于血清，表明SAA在脑组织水平而不是整个循环系统起作用。综上所述，在缺血/再灌注大鼠中，大量SAA进入中枢神经系统，促进其对紊乱代谢的保护和调节作用。
Salvianolic acid A (SAA), a water-soluble phenolic acid isolated from the root of Dan Shen, displays distinct antioxidant activity and effectiveness in protection against cerebral ischemia/reperfusion (I/R) damage. However, whether SAA can enter the central nervous system and exert its protective effects by directly targeting brain tissue remains unclear. In this study, we evaluated the cerebral protection of SAA in rats subjected to transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. The rats were treated with SAA (5, 10 mg/kg, iv) when the reperfusion was performed. SAA administration significantly decreased cerebral infarct area and the brain water content, attenuated the neurological deficit and pathology, and enhanced the anti-inflammatory and antioxidant capacity in tMCAO rats. The concentration of SAA in the plasma and brain was detected using LC-MS/MS. A pharmacokinetic study revealed that the circulatory system exposure to SAA was equivalent in the sham controls and I/R rats, but the brain exposure to SAA was significantly higher in the I/R rats than in the sham controls (fold change of 9.17), suggesting that the enhanced exposure to SAA contributed to its cerebral protective effect. Using a GC/MS-based metabolomic platform, metabolites in the serum and brain tissue were extracted and profiled. According to the metabolomic pattern of the tissue data, SAA administration significantly modulated the I/R-caused perturbation of metabolism in the brain to a greater extent than that in the serum, demonstrating that SAA worked at the brain tissue level rather than the whole circulation system. In conclusion, a larger amount of SAA enters the central nervous system in ischemia/reperfusion rats to facilitate its protective and regulatory effects on the perturbed metabolism.