摘要
目的观察甲硫哒嗪损伤大鼠学习记忆是否伴随脑内β-淀粉样蛋白(β-amyloid protein,Aβ)水平的升高,探讨甲硫哒嗪引起认知功能受损的机制。方法20只大鼠随机分为对照组和甲硫哒嗪组,连续2wk分别腹腔注射生理盐水和治疗剂量的甲硫哒嗪(10mg·kg-1)。用Morris水迷宫测定大鼠学习记忆能力,用放射免疫分析法测脑组织Aβ含量,用免疫组织化学染色检测β-淀粉样前体蛋白(β-amyloid precursor protein,APP)表达,用RT-PCR方法测定脑中3种APP、α及β-分泌酶mRNA表达。结果甲硫哒嗪组大鼠学习记忆能力下降,脑组织Aβ含量升高(P<0.05),是对照组的1.3倍;脑皮质和海马区APP蛋白表达增高(P<0.05);除APP695、α-分泌酶mRNA表达变化无统计学意义外,脑组织APP751和APP770 mRNA表达升高(P<0.05),相对表达量之和是对照组的2.5倍;β-分泌酶mRNA表达升高(P<0.05),是对照组的2.6倍。结论脑内Aβ水平的增加,可能是甲硫哒嗪引起认知功能损害的原因之一。
Aim To explore the molecular mechanism of interrelationship between thioridazine-induced learning and memory decline and the production of β-amyloid （Aβ） in the rat brain. Methods Male SpragneDawley rats were injected intraperitoneally with thioridazine of 10 mg · kg^-1 · d^-1 for 2 weeks in order to suppress cognition by inhibition of dopamine, acetylcholine and 5-hydroxytryptamine receptors. Morris water maze was used to measure spatial learning and memory performance. The Aβ content of brain was measured by radioimmunoassay. Immunohistochemistry was employed to determine β-amyloid precursor protein （APP） level. The mRNA levels of APP, β-secretase and α-secretase in brain were detected by RT-PCR. Results Thioridazine treatment to rats resulted in spa-tial learning and memory impairment shown by longer escape latency. Total Aβ was significantly increased by 1.3 times in thioridazine-treated rats. APP-immunoreactivities in cortex and hippocampus of thioridazinetreated rats were more pronounced than those of control rats. Levels of APP751 plus APP770 mRNA, β-secretase mRNA in brain increased nearly 2. 5 and 2. 6 folds respectively in thioridazine treated-rats, but no differences in mRNA levels of APP695 and α-secretase were found between thioridazine-treated and control rats. Conclusion The thioridazine-induced cognitive decline is related to the increase of Aβ caused by elevation of APP751 , APP770 and β-secretase expression.
出处
《中国药理学通报》
CAS
CSCD
北大核心
2007年第3期317-320,共4页
Chinese Pharmacological Bulletin
基金
国家自然科学基金(No30371566)
河北省自然科学基金(No303472)资助课题
