度洛西汀抗抑郁活性评价及毒性研究

目的评价5-HT/NE双重重摄取抑制剂度洛西汀的抗抑郁活性及毒性作用,为抗抑郁剂阳性药剂量选择及同靶标新药研发提供实验依据。方法采用小鼠悬尾和小鼠强迫游泳两个经典的行为绝望模型,对灌胃和腹腔注射两种途径给予度洛西汀的抗抑郁活性进行评价;采用小鼠急性毒性试验评价灌胃和腹腔注射两种途径给予度洛西汀的毒性;采用CCK-8试剂盒比色法检测度洛西汀对HepG2细胞存活的影响。结果灌胃或腹腔注射给予度洛西汀均可剂量依赖性缩短小鼠悬尾和游泳不动时间,有效剂量范围内无中枢兴奋作用;急性毒性试验结果表明,灌胃或腹腔注射给予度洛西汀的LD50值分别为177.1mg·kg-1和75.5mg·kg-1;细胞毒性结果表明,度洛西汀可浓度依赖性降低HepG2细胞的存活率,IC50为68.8μmol·L-1。结论度洛西汀抗抑郁作用明确而稳定,急性毒性主要与中枢神经系统药理作用有关,对胃肠道可能存在潜在不良反应。

Pharmacodynamic and toxicological evaluation of duloxetine

Aim To evaluate the antidepressant activity and toxicity of duloxetine,a serotonin and noradrenaline reuptake inhibitor.Methods Tail suspension test and forced swimming test in mice were used to evaluate the antidepressant activity of duloxetine,and acute toxicity test in mice and CCK-8 chromatometry were applied to investigate the general toxicity and cytotoxicity of duloxetine.Results In the tail suspension test and forced swimming test in mice,both oral and intraperitoneal administration of duloxetine reduced the immobility time in a dose-dependent manner,without a stimulant effect on the locomotor activity.The medial lethal dose of acute oral or intraperitoneal administration of duloxetine was 177.1 mg·kg-1 and 75.5 mg· kg-1,respectively,and the in vitro IC50 to HepG2 cell was 68.8 μmol·L-1.Conclusion Duloxetine exerted an excellent antidepressant effect,and the acute toxicity response was mainly related to CNS,with potential side effect on the gastrointestinal tract.