Study Of The Relationship Between Exercise And Memory Decline Induced By Aromatase Inhibitors

Abjective:Aromatase inhibitors have been widely used in the treatment for breast cancer.However, due to the inhibiting effects of aromatase inhibitors on estrogen, breast cancer patients often reported cognitive decline because of estrogen deficiency in brain. The improvement of exercise on cognition damage has been confirmed.Moreover, animal studies has proved that exercise could restore the cognitive decline caused by ovariectormy. However, few studies discuss the effects of exercise on aromatase inhibitor induced cognitive decline. So, this study aimed to absorve the effects of moderate exercise on cognitive decline induced by aromatase inhibitors.Methods:We used ovariectomized mouse to establish menopause animal model and divided animals into 5 groups:(1) ovariectomy+ vehicle+ sedentary(OVX+VEH+SED);(2) ovariectomy+ letrozole+ sedentary(OVX+LET+SED);(3)sham+ vehicle+ sedentary(SHAM+VEH+SED);(4) ovariectomy+ vehicle+ exercise(OVX+VEH+EX);(5) ovariectomy+ letrozole+ exercise(OVX+LET+EX). 2 weeks after ovariectomy, mice in the groups OVX+LET+SED and OVX+VEH+EX were given intraperitoneal injections of letrozole for 4 weeks(80μg/kg) to establish cognitive damage animal model. At the same time, mice in the groups of exercise received 4-weeks forced treadmill exercise training(10m/min, 1h/day). And then, we used Y maze and Morris water maze to detect working memory and spatial memory respectively. 24 hours after behavior tests, all the animals were sacrificed by anesthesia, serum and brain were collected. EIA were used to detect serum estrogen level and western blot were used to test the expression of BDNF, transcription factor CREB and p-CREB in prefrontal cortex and hippocampus respectively.Results:(1) The level of serum estradiol in group OVX+VEH+SED is significantly lower than that in group SHAM+VEH+SED(p>0.05).(2) There were no difference among animals received letrozole( OVX+LET+SED and OVX+LET+EX) or vehicle injections(OVX+VEH+SED and OVX+VEH+EX) on working memory tests.(3)Compared with animals in group OVX+VEH+SED and group OVX+VEH+EX, animals in group of OVX+LET+SED and OVX+LET+EX showed similar performance in spatial learning tests(p<0.01).(4) In the probe trails, animals received letrozole(OVX+LET+SED and OVX+LET+EX) had shorter duration in the target quarter than animals receivedvehicle injections(OVX+VEH+SED and OVX+VEH+EX)(p<0.05). And animals in group OVX+LET+SED had lesser entrances to the platform than animals in group OVX+VEH+SED(p<0.0125). There is no difference between OVX+LET+SED,OVX+LET+EX and OVX+VEH+SED, OVX+VEH+EX in the performance of target latency.(5) BDNF expression and level of p-CREB/CREB in hippocampus of animals injected letrozole are much lower than that injected vehicle(p<0.05). There were no difference of the expression of protein above in prefrontal cortex among groups. And exercise had no infect on the expression of BDNF and p-CREB/CREB in both areas(p > 0.05).Conclusion:(1) The impairments of aromatase inhibitors have specificity. Lack of estrogen would induce long-term spatial memory decline but working memory.(2) The impairments of hippocampus-dependent memory induced by aromatase inhibitor was related to the declined expression of BDNF and level of p-CREB/CREB in hippocamous.(3) 4 weeks moderate treadmill exercise could not reverse estrogen deficiency induced-memory decline.