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PK-PD Correlation of Erigeron Breviscapus Injection in the Treatment of Cerebral Ischemia-Reperfusion Injury Model Rats.
Journal of Molecular Neuroscience ( IF 2.8 ) Pub Date : 2020-08-05 , DOI: 10.1007/s12031-020-01651-3
Guangli Liu 1 , Guangmin Tang 2 , Weiwen Liang 3 , Zhang Wang 3 , Wenlong Xu 1 , Gang Fan 3 , Yujie Wang 3 , Mingming Zhao 1
Affiliation  

By measuring the cerebral infarction rate and neurological behavioral score of rats in a sham operation group, an MCAO model control group and an Erigeron breviscapus injection treatment group, we explored the therapeutic effects of Erigeron breviscapus injection on brain tissue and neuroethological injury in rats. Plasma samples were collected at 18 time points after intravenous injection of Erigeron breviscapus. The levels of scutellarin, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, chlorogenic acid and isochlorogenic acid B in rat plasma at the various time points were determined by an HPLC method, and drug concentration versus time plots were constructed to estimate the pharmacokinetic parameters. Finally, a PK-PD combined model was used to analyze the relationship between the blood concentration, time and therapeutic effects of the seven active components. The results of the pharmacodynamics studies showed that the cerebral infarction rate of rats in the Erigeron breviscapus injection group decreased significantly at 5 min, 10 min, 20 min, 6 h, 8 h, 18 h, 24 h, 32 h, 40 h and 48 h after cerebral ischemia. Abnormal neurological behavior scores were significantly reduced after 4 h of cerebral ischemia. The pharmacokinetics results showed that the seven chemical constituents in Erigeron breviscapus injection reached their highest detection value after 5 min of cerebral ischemia. The lowest detection values of scutellarin and isochlorogenic acid B appeared after 6 h of cerebral ischemia but could not be detected after 8 h. The lowest detection values of 5-caffeoylquinic acid and 4,5-dicaffeoylquinic acid were found in the third hour of cerebral ischemia but not after 4 h. The lowest detection values of 4-caffeoylquinic acid, 3,5-dicaffeoylquinic acid and chlorogenic acid were found during the second hour of cerebral ischemia but not at the third hour. However, at 18 h, 24 h, 32 h and 40 h of cerebral ischemia, the cerebral infarction rates of rats in the Erigeron breviscapus injection group were significantly reduced, with decreased values of 6.22%, 11.71%, 6.92% and 4.96%, respectively, and the effects were stronger than those after 5–20 min of cerebral ischemia. The decreased values reached their highest value after 24 h of cerebral ischemia. Our results show that the effects of Erigeron breviscapus injection on reducing the cerebral infarct rate in MCAO model rats are characterized by a fast onset and long maintenance time. The 5-min blood concentration in cerebral ischemia was the highest test value, and after this time, the cerebral infarction rate of MCAO rats began to decrease. However, the peak value of the effects lagged behind that of the plasma concentration. The maximum effective time for Erigeron breviscapus injection appeared 24 h after cerebral ischemia, which provides a reference for the screening of specific drugs for ischemic stroke, optimal dosing regimens and rational clinical drug use.

Graphical Abstract



中文翻译:

灯盏细辛注射液治疗脑缺血再灌注损伤模型大鼠的PK-PD相关性。

通过测量假手术组、MCAO模型对照组和灯盏细辛注射液治疗组大鼠的脑梗死率和神经行为学评分,探讨灯盏花注射液对大鼠脑组织和神经行为学损伤的治疗作用。在静脉注射灯盏花后的 18 个时间点收集血浆样本. 采用高效液相色谱法测定不同时间点大鼠血浆中灯盏花乙素、4-咖啡酰奎宁酸、5-咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸、4,5-二咖啡酰奎宁酸、绿原酸和异绿原酸B的含量,构建药物浓度与时间图以估计药代动力学参数。最后采用PK-PD联合模型分析7种活性成分的血药浓度、时间与疗效的关系。药效学研究结果表明,灯盏细辛对大鼠脑梗塞率的影响注射组在脑缺血后5 min、10 min、20 min、6 h、8 h、18 h、24 h、32 h、40 h和48 h显着下降。脑缺血4小时后,异常神经行为评分显着降低。药代动力学结果表明灯盏花中的七种化学成分脑缺血5分钟后注射液达到最高检测值。灯盏花乙素和异绿原酸 B 检测值最低出现在脑缺血 6 h 后,8 h 后检测不到。5-咖啡酰奎宁酸和4,5-二咖啡酰奎宁酸的最低检测值出现在脑缺血的第3小时,而不是4小时后。4-咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸和绿原酸的最低检测值出现在脑缺血的第二小时,而在第三小时则没有。而在脑缺血18 h、24 h、32 h和40 h,灯盏灯大鼠脑梗塞率注射组显着降低,分别降低6.22%、11.71%、6.92%和4.96%,且作用强于脑缺血5-20 min后。脑缺血 24 小时后降低值达到最高值。我们的研究结果表明灯盏花注射液对降低 MCAO 模型大鼠脑梗死率的作用具有起效快、维持时间长的特点。脑缺血5min血药浓度为最高试验值,此后MCAO大鼠脑梗死率开始下降。然而,效应的峰值滞后于血浆浓度的峰值。灯盏花的最长有效时间 脑缺血后24 h出现注射液,为缺血性脑卒中特异性药物的筛选、最佳给药方案和临床合理用药提供参考。

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更新日期:2020-08-05
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