Thioridazine-induced learning and memory decline is accompanied by elevation of ?-amyloid in rat brain / 中国药理学通报

ABSTRACT

Aim To explore the molecular mechanism of interrelationship between thioridazine-induced learning and memory decline and the production of ?-amyloid (A?) in the rat brain. Methods Male Sprague-Dawley 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 A? content of brain was measured by radioimmunoassay. Immunohistochemistry was employed to determine ?-amyloid precursor protein (APP) level. The mRNA levels of APP,?-secretase and ?-secretase in brain were detected by RT-PCR. Results Thioridazine treatment to rats resulted in spatial learning and memory impairment shown by longer escape latency. Total A? was significantly increased by 1.3 times in thioridazine-treated rats. APP-immunoreactivities in cortex and hippocampus of thioridazine-treated rats were more pronounced than those of control rats. Levels of APP751 plus APP770 mRNA,?-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 ?-secretase were found between thioridazine-treated and control rats. Conclusion The thioridazine-induced cognitive decline is related to the increase of A? caused by elevation of APP751,APP770 and ?-secretase expression.