Chi Xiaowei, Yu Dan, Li Peijing, Lu Qianfeng, Jiang Wenjiao, Hao Kun
School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China; Weifang Biomedical Innovation and Entrepreneurship Service Center, Weifang 261205, China.
Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Eur J Pharm Sci. 2017 Mar 30;100:94-101. doi: 10.1016/j.ejps.2016.12.042. Epub 2017 Jan 3.
The relationship between the chemistry characteristic and the hepatoprotective effects of (1E,6E)-1,7-diphenylhepta-1,6-diene-3,5-dione (DDD), a curcumin analogue, in operative liver injury rats was investigated to reveal the mechanism of hepatic protection effects of DDD. DDD (1.2-4.8mmol/kg) was administrated 10min before reperfusion phase in hepatic ischemia-reperfusion injury (IRI) rats. DDD (4.8mmol/kg) administrated 10min before ischemia and N-acetylcysteine (NAC) (4.8mmol/kg) administrated 10min before reperfusion were included for comparative studies. The plasma liver enzyme activities, histopathological indices and markers of lipid peroxide were determined to evaluate the hepatic protection effects. Effects of DDD on succinate dehydrogenase (SDH) activity were also investigated. DDD showed dose-dependent hepatocyte protections when administrated 10min before reperfusion stages in hepatic IRI rats. DDD showed almost equivalent hepatoprotective effects when administrated 10min before ischemia phase demonstrating that DDD acted on the reperfusion stages selectively against the hepatic IRI, instead of ischemia phase. NAC was not effective against hepatic IRI when treated 10min before reperfusion because of the higher pKa of NAC. In additional, DDD had no effect on the SDH both in hepatic IRI rats and in mitochondria. In conclusion, DDD had dose-dependent hepatocyte protections in the reperfusion stages in hepatic IRI rats, while the observed hepatocyte protections of DDD did not involve SDH activities. β-Diketone structures of DDD were crucial for the hepatocyte protections. The abilities of DDD to clear up the unsaturated aldehydes related with the enolate nucleophilicity and the pKa. DDD might be a promising candidate to treat hepatic IRI.
研究姜黄素类似物（1E,6E）-1,7-二苯基庚-1,6-二烯-3,5-二酮（DDD）的化学特性与对手术性肝损伤大鼠肝保护作用之间的关系，以揭示DDD肝保护作用的机制。在肝缺血再灌注损伤（IRI）大鼠的再灌注阶段前10分钟给予DDD（1.2 - 4.8mmol/kg）。包括在缺血前10分钟给予DDD（4.8mmol/kg）和在再灌注前10分钟给予N-乙酰半胱氨酸（NAC）（4.8mmol/kg）进行对比研究。测定血浆肝酶活性、组织病理学指标和脂质过氧化标志物以评估肝保护作用。还研究了DDD对琥珀酸脱氢酶（SDH）活性的影响。在肝IRI大鼠的再灌注阶段前10分钟给予DDD时，显示出剂量依赖性的肝细胞保护作用。在缺血阶段前10分钟给予DDD时显示出几乎等效的肝保护作用，表明DDD选择性作用于再灌注阶段以对抗肝IRI，而非缺血阶段。由于NAC的pKa较高，在再灌注前10分钟治疗时，NAC对肝IRI无效。此外，DDD对肝IRI大鼠和线粒体中的SDH均无影响。总之，DDD在肝IRI大鼠的再灌注阶段具有剂量依赖性的肝细胞保护作用，而观察到的DDD的肝细胞保护作用不涉及SDH活性。DDD的β-二酮结构对肝细胞保护至关重要。DDD清除与烯醇负离子亲核性和pKa相关的不饱和醛的能力。DDD可能是治疗肝IRI的有前途的候选药物。
