Study On The Effects And Mechanism Of Icariin In Rats’ Learning And Memory Deficits Induced By Tamoxifen

Alzheimer’s disease (AD) is a degenerative disease of the centralnervous system. It is characterized by long-term memory loss, cognitivedeficits and abnormal behavior. The main typical pathological changes of ADare cortical atrophy, with the deposition of β-amyloid protein (β-amyloidprotein, Aβ), formation of senile plaques (Seile plaque, SP), neurofibrillarytangles (Neuro fibrillary tangles, NFT), and the loss of neurons in cerebralcortex and certain subcortical regions. Among the factors causing the death ofthe senior, it has become the top4th killer worldwide. There is a greatdifference in the epidemiologicl statisitcs of AD between male and female.Usually the morbidity of AD in women is2or3times higher than that in men,suggesting that the estrogen plays a crucial role in preventing the occurrenceand the development process of AD. Icariin (ICA) is a flavonoid extractedfrom the medicinal plant Epimedium. Recent studies have shown that ICA hasan obvious estrogenic effect and also improved the aluminum toxicity, whichwould induce learning and memory impairment in rats, which indicated thatICA may be a potential drug candidate for the treatment of AD.Tamoxifen (TC) is a selective estrogen receptor modulator which caninterfere estrogen activities and simulate other estrogenic effects. It is oftenused in the treatment of some breastand ovarian cancer.Studies have shownthat breast cancer patients who were treated by using chemotherapy drugsadjuvantly with selective estrogen receptor modulators such as tamoxifencould exhibit symptoms of memory impairment. In this study, learning andmemory impairment model of SD female rats was established byintraperitoneal injection of TC. Morris water maze test, step-down test and 8-arm maze task were used to test the effect of tamoxifen on learning andmemory abilities of female SD rats. The uterus coefficient, serum estradiollevels, the cerebral cortex cholinergic indicators and estrogen receptor gene ofcerebral cortex and hippocampus which are learning and memory-relatedindicators were also detected. Then, on the basis of the learning and memoryimpairment model induced by TC intraperitoneal injection, we furtherinvestigated the effects of ICA on the learning and memory impairments.Morris water maze test, step-down test and8-arm maze task were used to testthe function of ICA on the learning and memory impairment of female SDrats. The uterus coefficient, serum estradiol levels, the cerebral cortexcholinergic indicators and estrogen receptor gene of cerebral cortex andhippocampus which are learning and memory-related indicators were alsoabserved.The results showed that:1.(1) Female SD rats were given intraperitonealinjection of TC2.5mg/kg,5mg·kg-1, and10mg·kg-1, which can causelearning and memory disorders. The results of Morris water maze testsuggested that, compared with rats in control group, the time to find theplatform (escape latency) of rats in TC treatment groups was significantlyprolonged in place navigation trail, and the first time through platform andpercentage of time spent in target quadrant were decreased in probe trails. Theresults of step-down test indicated that compared with rats in control group,the number of errors was increased while the escaping latency was decreasedin TC treatment groups.8-arm maze task revealed that path and typical faultsof rats in TC treatment groups were obviously increased.(2) The serumconcentration of estradiol and the uterus coefficient in SD female rats werereduced after intraperitoneal injection of TC2.5mg·kg-1,5mg·kg-1and10mg·kg-1.(3) The content of TCHE and the activity ration of ChAT/AChE incortex of SD female rats were decreased after intraperitoneal injection of TC2.5mg·kg-1,5mg·kg-1and10mg·kg-1.(4) The gene expression ration of ER-α/ER-β in both cortex and hippocampus of SD female rats were loweredafter intraperitoneal injection of TC2.5mg·kg-1,5mg·kg-1and10mg·kg-1.2.(1) After oral administration of ICA25mg·kg-1,50mg·kg-1and100mg·kg-1,learning and memory deficits caused by TC injection could be improved inSD female rats. The results of Morris water maze showed that compared withrats in TC group, the escape latency of rats in ICA treatment groups weresignificantly shortened in place navigation trail and the first time throughplatform and percentage of time spent in target quadrant were increased inprobe trails. The results of step-down test indicated that compared with rats inTC group, the number of errors was decreased and the escaping latency wasincreased in ICA treatment grous.8-arm maze task revealed that path andtypical faults were both cut down in ICA treatment groups compared with ratsin TC group.(2) The serum concentration of estradiol and the uteruscoefficient in SD female rats were increased after oral administration of ICA25mg·kg-1,50mg·kg-1and100mg·kg-1compared with rats in TC group.(3)The content of TCHE and the activity ration of ChAT/AChE in cortex of SDfemale rats were increased after oral administration of ICA25mg·kg-1,50mg·kg-1and100mg·kg-1compared with rats in TC group.(4) The geneexpression ration of ER-α/ER-β in both cortex and hippocampus of SDfemale rats were increased after oral administration of ICA25mg·kg-1,50mg·kg-1and100mg·kg-1compared with rats in the model group.These results indicated that,(1) TC injection can cause learning andmemory deficits in female SD rats and its brain impariment was related to theestrogen receptor antagonist.(2) With the estrogen-like effect, ICA treatmentcan improve TC injection, inducing learning and memory impairments.