红景天苷衍生物对抗抑郁及促学习记忆作用的影响

The antidepressive and ameliorating cognitive impairment effects of a salidroside amide derivative

目的通过大、小鼠体内药动学研究,寻找成药性较好的红景天苷衍生物,并采用动物体内药效模型初步评价该化合物改善学习记忆及抗抑郁的作用。方法设计并合成了一系列红景天苷酰胺衍生物(5a^5e),通过大鼠体内药代动力学研究,找到入脑迅速目标化合物(5c),后续以东莨菪碱造成大鼠记忆获得障碍模型,研究不同剂量5c(20、5、1.25 mg/kg)和红景天苷(20、5、1.25 mg/kg)对该模型大鼠学习记忆改善作用;以小鼠悬尾实验中小鼠不动时间,研究不同剂量5c(50、25、12.5 mg/kg)及红景天苷(25 mg/kg)的抗抑郁作用。结果大鼠药代动力学的成药性评价显示,单次口服给予25 mg/kg 5c后,约1.4 h达峰,生物利用度为33.3%(优于红景天苷21.8%),口服吸收后可入脑,脑/血组织中的浓度为比为2.5。在大鼠记忆获得障碍模型Morris水迷宫撤台实验测试中,5c高剂量组(20 mg/kg)及盐酸多奈哌齐组大鼠第一次上台潜伏期及第一次穿台路程较模型对照组缩短,差异具有统计学意义(P <0.05)。大鼠脑部SOD活性测定结果显示,5c高剂量组(20 mg/kg)大鼠脑部SOD活性高于空白对照组,差异具有统计学意义(P <0.05),在小鼠悬尾实验中,在给药2 h的测试时间点,5c高剂量组小鼠悬尾不动时间较空白对照组缩短,差异具有统计学意义(P <0.05)。结论通过对红景天苷进行结构改造,得到了具有良好透过血脑屏障的能力红景天苷衍生物5c,体内药效学评价结果显示:该化合物具有抗抑郁及改善学习记忆的作用,且效果优于红景天苷。

Objective A rat pharmacokinetics study was done to search for salidroside amide derivatives with better pharmaceutical properties.The effects of the screened derivatives on improving cognition and antidepression were preliminarily evaluated by animal pharmacodynamics model.Methods A series of salidroside amide derivatives were designed and synthesized(5 a^5 e).Pharmacokinetics study of the rats was used to found target compound(5 c)that can enter into brain quickly.Thereafter,a rat model of memory acquisition disorder induced by scopolamine was established to study the effects of different doses of 5 c(20,5 and 1.25 mg/kg)and salidroside(20,5 and 1.25 mg/kg)on learning and memory of the model rats.The antidepressant effects of different doses of 5 c(50,25 and 12.5 mg/kg)and salidroside(25 mg/kg)on mice were studied in tail suspension test measured as immobilization time.Results The pharmaceutical property of pharmacokinetic evaluation showed that after oral administration of 25 mg/kg 5 c,blood level reached peak at about 1.4 h,the bioavailability of salidroside was 33.3%(higher than 21.8%of salidroside).After oral administration,salidroside can be absorbed into brain and the concentration ratio of brain/blood was 2.5.In Morris water maze withdrawal test of rat model,the first incubation period and the first crossing distance of rats in high dose 5 c group(20 mg/kg)and donepezil hydrochloride group were shorter than those in model control group,and the differences were statistically significant(P<0.05).The measurement of rat brain SOD activity showed that activity of SOD in brain of rats in 5 c high dose group(20 mg/kg)was higher than that in blank control group,and the differences were statistically significant(P<0.05).In the tail suspension test of mice,two hours after administration,the tail suspension immobilization time of mice in5 c high dose group was shorter than that in blank control group,and the differences were statistically significant(P<0.05).Conclusion Salidroside has been reconstructed to develop the derivatives 5 c,that had better ability to go though bloodbrain barrier.In vivo pharmacokinetic evaluation shown that this chemical had antidepressant and ameliorating cognitive impairment effects and the efficacy was better than salidroside.