纳洛酮对三氯化铝致急性衰老小鼠记忆障碍的保护作用及其机制

背景老年性痴呆患者脑细胞中铝的含量普遍增高.大脑铝中毒与老年性痴呆有一定内在联系.纳洛酮是阿片受体特异性拮抗剂,国外有用于老年性痴呆治疗的报道.目的探讨纳洛酮对三氯化铝所致急性衰老小鼠记忆障碍的保护作用及其机制.设计随机对照观察.单位吉林医药学院.材料实验于2001-02/2003-02在吉林医药学院(原吉林军医学院)药理学实验室完成,选择健康成年昆明种小鼠100只,随机分为5组,每组20只,即对照组,模型组,纳洛酮0.1,0.3,0.9mg/kg组,除对照组外,每组小鼠每天皮下注射1次氯化铝70 mg/kg,连续注射7 d;纳洛酮组每只鼠除皮下注射氯化铝外,腹腔分别注射纳洛酮0.1,0.3,0.9 mg,/kg,对照组皮下注射等量的生理盐水.方法用跳台、避暗等实验方法测定小鼠学习记忆能力,同时测定小鼠肝丙二醛、脑B型单胺氧化酶的含量.主要观察指标①三氯化铝所致衰老模型跳台实验结果.②三氯化铝所致急性衰老模型避暗法实验结果.③各组丙二醛和B型单胺氧化酶的比较.结果①三氯化铝所致衰老模型跳台实验结果与模型组相比较,对照组及纳洛酮0.1,0.3,0.9 mg/kg剂量组能够明显减少三氯化铝小鼠5 min内受电击次数和受电击的动物数,24 h重复实验,纳洛酮能够明显延长小鼠第1次跳下平台潜伏期(P＜0.01),同时,纳洛酮能够降低三氯化铝小鼠3 min内错误总数和错误频率(P＜0.01).②三氯化铝所致急性衰老模型避暗法实验结果与模型组相比,对照组及纳洛酮0.1,0.3,0.9 mg/kg剂量组能够明显延长三氯化铝小鼠进入暗箱的潜伏期及小鼠5 min内受电击次数(P＜0.01).③各组丙二醛和B型单胺氧化酶的比较模型组丙二醛明显高于对照组和纳洛酮各剂量组(P＜0.01).模型组B型单胺氧化酶活性明显高于其他各组(P＜0.01).结论纳洛酮对三氯化铝所致急性衰老小鼠记忆障碍具有保护作用,能增强学习记忆能力.其作用机制可能和降低B型单胺氧化酶、清除过氧化脂质作用有关.

Investigation of protective effects of naloxone on aluminium trichloride-induced memory impairment of senescence-accelerated mice and its mechanism

BACKGROUND: The content of aluminium generally increases in the cerebral cells of patients with senile dementia. Aluminium poisoning in brain has inner link with senile dementia. Naloxone is the specific antagonist of opioid receptor, which can be applied in the treatment of senile dementia according to foreign reports.OBJECTIVE: To investigate protective effects of naloxone on aluminium trichloride-induced memory impairment of senescence-accelerated mice and its mechanism.DESIGN: Randomized controlled trial.SETTING: Jilin Medical College.MATERIALS: The experiment was completed in Laboratory of Pharmacology of Jilin Medical College (formerly the Jilin Military Medical College) from February 2001 to February 2003. A total of 100 healthy adult Kunming mice were selected and randomly divided into 5 groups: control group, model group, naloxone 0.1 mg/kg group, naloxone 0.3 mg/kg group and naloxone 0.9 mg/kg group, with 20 in each group. Except the control group, subcutaneous injection with 70 mg/kg aluminium trichloride was given to the mouse in each group once a day for continuous 7 days; besides this, intraperitoneal injection with 0.1, 0.3, 0.9 mg/kg naloxone was given to the mouse in naloxone groups and the same amount of physiological saline was given to the mouse in the control group.METHODS: The methods of jumping stand and escaping dark were conducted to detect learning ability and memory of mice. Meanwhile, the content of malondialdhehyde in liver and mono-amine oxidase B in brain of mice were also detect.MAIN OUTCOME MEASURES: ① Results of jumping stand experiment of aluminium trichloride-induced model of senescence. ② Results of escaping dark experiment of aluminium trichloride-induced model of senescence. ③ Comparison of malondialdhehyde and mono-amine oxidase B among each group.RESULTS: ① Results of jumping stand experiment of aluminium trichloride-induced model of senescence: Compared withmodel group, the frequency of electric shocks suffered by aluminium trichloride mice and the amount of suffered animals within 5 minutes significantly decreased in control group and naloxone 0.1, 0.3, 0.9 mg/kg groups. The experiment was repeated 24 hours later, naloxone could significantly prolong the latency of the mouse jumping down from the platform for the first time (P ＜ 0.01).Meanwhile, naloxone could decrease the amount and the frequency of mist&es of aluminium trichloride mouse within 3 minutes (P ＜ 0.01). ② Results of escaping dark experiment of aluminium trichloride-induced model of senescence: Compared with model group, the latency of aluminium trichloride mouse entering dark box was significantly prolonged and the frequency of electric shocks suffered by aluminium trichloride mice obviously increased in control group and naloxone 0.1, 0.3, 0.9 mg/kg groups (P＜0.01). ③ Comparison of malondialdhehyde and mono-amine oxidase B among each group: Malondialdhehyde was more in model group than in naloxone groups (P＜0.01). Mono-amine oxidase B was more in model group than in the other groups (P＜0.01).CONCLUSION: Naloxone has protective effects on aluminium trichlorideinduced memory impairment of senescence-accelerated mice, which can improve learning ability and memory. The mechanism is probably relevant to the effects of decrease of mono-amine oxidase B and elimination of lipid peroxide.