| Estrogen receptors in the central nervous system affect learning and memory function with various extent. Selective estrogen receptor modulators, such as tamoxifen, toremifene and raloxifene, are frequently used in treatment and prevention of breast cancer in women. Raloxifene is also used in prevention and treatment of osteoporosis in postmenopausal women. However, effects of these drugs on the central nervous system, especially on memory function, have rarely been reported detailedly and systematically.In the present study, by using behavioral tests, it was demonstrated that tamoxifen (1-10 mg/kg), toremifene (3-30 mg/kg) and raloxifene (3-30 mg/kg) with a single intraperitoneal administration significantly shortened the escaping latency and increased the number of errors, respectively, in step-down and step-through passive avoidance tests in female mice. Tamoxifen and toremifene significantly delayed the latency of finding food in an appetitively-motivated task in T-maze in well-trained female mice. When tested in the spatial information by tamoxifen, toremifene and raloxifene also shortened the time spent in target quadrant in Morris water maze. According to above results, it seems that tamoxifen mainly impairs memory consolidation and retrieval processes, toremifene impairs acquisition, consolidation and retrieval processes and raloxifene mainly impairs acquisition and retrieval processes. Compared with the other two drugs, the potency of impairment induced by raloxifene was much weaker.The impairment of memory function caused by tamoxifen was clearly time dependent. The maximal effect of tamoxifen on memory retrieval in step-down test was observed 30 min after drug administration and the effect disappeared in 3 hours. Those results were consistent with the character ofpharmacokinetic process of tamoxifen in hippocampus and frontal cortex of female mice.The pharmacokinetic behavior of tamoxifen in hippocampus and frontal cortex of the mouse was detected by using brain microdialysis coupled to HPLC with fluorescence detection. It was shown that the peak concentration of tamoxifen in hippocampus and frontal cortex was reached 30-45 min after intraperitoneal drug administration. The half life in hippocampus or frontal cortex was 83.84 min and 115.6 min, and the value of ke was 0.008 min-1 and 0.006 min-1 respectively.Drug interaction studies showed that estradiol (1.6 mg/kg, s.c.) significantly antagonized the action of tamoxifen in passive avoidance condition and in memory retrieval process of spatial information. Physostigmine, an inhibitor of cholinesterase, and oxotremorine, a nonselective muscarinic receptor agonist, could also antagonize the impairing effect of tamoxifen in passive or active avoidance condition and in memory retrieval process of spatial information. The above results suggest that the machanisms of impairing memory function of tamoxifen are partially due to its inhibitory effects on estrogenic receptors and the central cholinergic system.Ginseng stem-leaves saponins (100-200 mg/kg) and pseudoginsenoside-F11 (2-4 mg/kg) also antagonized tamoxifen-induced or toremifene-induced impairment in passive or active avoidance condition and in memory retrieval process of spatial information. But piracetam (150-300 mg/kg) and nimodipine (5-10 mg/kg) showed no effect.It was also demonstrated that tamoxifen (2 g/ml) and toremifene (2 g/ml) had antiproliferative effect and induced apoptosis in MCF-7 breast cancer cell lines by using MTT method and flow cytometry. The antiproliferative effect and apoptosis-inducing effects of tamoxifen and toremifene were enhanced by ginseng stem-leaves saponins (10-20g/ml),pseudoginsenoside-F11 (0.2-0.4g/ml), piracetam (15-30g/ml) and nimodipine (0.5-1g/ml) respectively.Taken together, the present study provides first and systematical evidence that selective estrogen receptor modulators, tamoxifen, toremifene and raloxifene, could impair learning and memory function in mice. The mechanism of impairin...
|
PDF Full Text Request