尼古丁对Aβ25-35诱导学习记忆障碍小鼠的治疗作用

The therapeutic effects of nicotine in Aβ_(25-35)-induced Alzheimer's disease models

目的探讨nAChR激动剂尼古丁对β-淀粉样蛋白(Aβ25-35)诱导的学习记忆障碍小鼠模型的治疗作用以及可能的作用机制。方法小鼠侧脑室注入凝聚态Aβ25-354.5μl。次日,用药组给予尼古丁0.2和2 mg.kg-1(ip,bid×7d),对照组及模型组ip生理盐水。给药结束4 d后(造模成功后11 d),进行各组行为学及皮层、海马组织乙酰胆碱酯酶(AChE)、胆碱乙酰转移酶(ChAT)、丙二醛(MDA)、谷胱甘肽(GSH)活性指标的检测。结果定位航行实验发现,训练d 4,模型组小鼠的上台潜伏期和游泳距离明显高于对照组和0.2、2 mg.kg-1尼古丁治疗组(P<0.01);空间搜索实验发现,实验d 5撤除平台,模型组在平台所在象限(第Ⅱ象限)中游泳的时间百分比明显低于对照组(P<0.01)和0.2及2 mg.kg-1尼古丁治疗组(P<0.05);模型组在平台所在象限(第Ⅱ象限)中游泳的距离百分比明显低于对照组(P<0.01),但与0.2及2 mg.kg-1尼古丁治疗组无差别(P>0.05)。酶活性检测发现尼古丁治疗组的AChE及ChAT的活性较对照组明显升高(P<0.01);尼古丁治疗组(2 mg.kg-1)MDA的活性较模型组明显降低(P<0.01),尼古丁治疗组(0.2 mg.kg-1)的活性较模型组无改变(P>0.05);尼古丁治疗组的GSH活性较模型组明显升高(P<0.01)。结论尼古丁能够改善Aβ25-35诱导痴呆小鼠的学习记忆功能障碍,该作用与其增强ChAT的活性以及抗氧化应激有关。

Aim To investigate the effects of nAChR agonist -nicontine in a mice model of Alzheimer＇s dis- ease（AD） rendered by Aβ25-35. Methods Mice were administered nicotine （0. 2,2 mg · kg - 1 ip, bid） for 7 d and control mice received daily ip injections of saline after the intracerebroventricular injection of aggregated Aβ25-35. After the last treatment, passive avoidance and performance in the Morris water maze （MWM） were assessed. The activities of cortical and hippocam- pal CHAT, ACHE, MDA and GSH were detected after the final behavioral test. Results Nicotine （ 0. 2, 2 mg·kg -1 ip, bid） significantly ameliorated the learn- ing and memory impairment induced by Aβ25-35. Nicotine （0. 2,2 mg · kg-1） decreased the latencies and swim distances of mice to reach a hidden platform and improved the corresponding changes in search strate- gies occurred in the Morris water maze. Biochemical a- nalysis showed that Nicotine （0. 2,2 mg· kg-1） pre- vented the decline of cortical and hippocampal ChAT and GSH activities induced by Aβ25-35, and showed in- hibition of the activity of MDA, although Aβ25-35 showed no effect on the cortical and hippocampal AChE activity compared with the Aβ25-35-induced mice groups. Conclusion Nicotine can reverse Aβ25-35-in- duced memory retrieval deficits in mice, and this effect was mediated by enhanced activity of ChAT and the inhibition of oxidative stress.