柴胡总皂苷对小鼠抑郁样行为及学习记忆障碍的改善作用

目的:研究柴胡总皂苷连续给药抗抑郁作用起效时间及作用维持时间,以及柴胡总皂苷对皮质酮损伤引起的小鼠抑郁样行为及认知功能障碍的影响。方法:ICR雄性小鼠随机分为正常组(蒸馏水)、柴胡总皂苷低剂量组(12.5 mg·kg~(-1)),柴胡总皂苷中剂量组(25 mg·kg~(-1)),柴胡总皂苷高剂量组(50 mg·kg~(-1))。每周称体重,给药13 d后,进行空场实验。给药14 d后1 h,3 d,6 d观察柴胡总皂苷对强迫游泳实验不动时间的影响。C57BL/6J雄性小鼠随机分为正常组,皮质酮组(CORT组),西酞普兰组(10 mg·kg~(-1))和柴胡总皂苷(25 mg·kg~(-1))组。CORT组、西酞普兰组和柴胡总皂苷组饮用皮质酮。造模3周后,ig给予柴胡总皂苷,给药时间为2周,至第5周结束,西酞普兰ig,给药时间同柴胡总皂苷。给药结束后1 d,进行强迫游泳实验和水迷宫实验。行为学实验结束后,各组各取3只小鼠,断头,取海马,蛋白质免疫印迹(Western blot)进行脑源性神经营养因子(BDNF)和酪氨酸激酶B(Trk B)蛋白表达检测。结果:柴胡总皂苷连续给药14 d,与正常组比较,对体重和空场实验运动路程及速度无影响。停药后1 h和3 d,柴胡总皂苷各剂量组均可缩短小鼠强迫游泳不动时间(P0.01,P0.05);停药后6 d,柴胡总皂苷25,50 mg·kg~(-1)仍可缩短小鼠强迫游泳实验不动时间(P0.05)。柴胡总皂苷25 mg·kg~(-1)连续给药14 d,可缩短皮质酮损伤小鼠强迫游泳不动时间(P0.01),缩短水迷宫实验寻台潜伏期(P0.05),提高穿台次数(P0.05),并增加皮质酮损伤小鼠海马BDNF和Trk B蛋白表达(P0.01)。结论:柴胡总皂苷连续给药产生较快而持久的抗抑郁作用,逆转皮质酮损伤引起的小鼠抑郁样行为及学习记忆障碍。其作用机制可能与增加小鼠海马BDNF及Trk B表达有关。

Effect of Total Saponins from Bupleuri Radix on Improvement in Depression-Like Behavior and Learning and Memory Ability in Mice

Objective: To investigate the onset time and duration of action for the antidepressant effect of total saponins from Bupleuri Radix, and observe their effects on corticosterone damage-induced depression behavior and learning and memory impairment in mice. Method: Male ICR mice were randomly divided into normal group (distilled water),total saponins from Bupleuri Radix low, middle and high dose groups (12.5,25,50 mg·kg^-1).They were weighed every week, and field experiment was conducted after drug administration for 13 days.Total saikosaponins was given intragastrically once a day for 14 consecutive days. The effects of total saponins from Bupleuri Radix on motionless time in forced-swimming test were observed after the last administration at different time (1 h, 3 d, 6 d). Male c57BL/6J mice were randomly divided into normal group, corticosterone (CORT) group, citalopram group (10 mg·kg^-1) and total saponins from Bupleuri Radix group (25 mg·kg^-1).Corticosterone (35 mg·L^-1, equivalent to 5 mg·kg^-1·d^-1) was delivered for 5 weeks in drinking water in CORT group, citalopram group and total saponins from Bupleuri Radix group.3 weeks after modeling,total saponins from Bupleuri Radix were given by ig administration for 2 weeks until week 5; citalopram was also given by ig administration for 2 weeks. 1 day after drug administration, forced swimming test and water maze test were conducted. After the behavioral experiment, 3 mice were taken from each group. They were sacrificed then,and hippocampus was taken to detect the expression levels of brain derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB)by Western blot. Result: As compared with the normal group, total saponins from Bupleuri Radix had no effects on weight and moving distance and velocity in field experiment after 14 days administration, but could decrease the motionless time in forced swimming test at different time (1 h and 3 d after drug with drawal) (P<0.05, P<0.01). 6 days after drug withdrawal, total saponins from Bupleuri Radix 25 and 50 mg·kg^-1 could still shorten the motionless time in forced swimming test (P<0.05). Two weeks treatment with total saponins from Bupleuri Radix at dose of 25 mg·kg decreased the motionless time in forced swimming test (P<0.01) and shorten the latency to reach the platform, and increase the number of platform crossing times in Morris Water Maze (P<0.05); in addition, they could increase the BDNF and Trk B levels in the hippocampus of mice with corticosterone damage (P<0.01). Conclusion: Total saponins from Bupleuri Radix could have a rapid and sustained antidepressant activity and reverse the depression-like behavior as well as learning and memory impairment induced by corticosterone damage. The mechanism may be associated withup-regulating BDNF and Trk B expression levels in the hippocampus of mice.