运动与芳香酶抑制剂诱发的记忆损伤关系研究

发布时间：2018-09-14 07:27

【摘要】：研究目的:芳香酶抑制剂广泛用于乳腺癌的治疗,然而由于芳香酶抑制剂对雌激素的抑制作用,导致乳腺癌患者大脑中雌激素的缺失,进而引发患者的认知功能损伤。运动对于认知功能的改善作用已得到广泛认可,同时,动物研究也已证实了运动对卵巢切除鼠的认知损伤具有修复作用。而运动对芳香酶抑制剂所诱发的认知损伤的作用还鲜有报道。本研究拟通过建立芳香酶抑制剂诱发的认知损伤动物模型,探讨中等强度有氧运动对芳香酶抑制剂诱发的认知损伤的作用。研究方法:采用卵巢切除术建立小鼠更年期模型,将3月龄雌性C57BL/6小鼠随机分为5组:(1)卵巢切除+赋形剂+安静组(OVX+VEH+SED);(2)卵巢切除+芳香酶抑制剂注射+安静组(OVX+LET+SED);(3)假手术+赋形剂+安静组(SHAM+VEH+SED);(4)卵巢切除+赋形剂+运动组(OVX+VEH+EX);(5)卵巢切除+芳香酶抑制剂注射+运动组(OVX+LET+EX)。卵巢切除2周后对芳香化酶抑制剂注射组小鼠进行为期4周的letrozole(80μg/kg)腹腔注射,建立小鼠认知障碍模型。与此同时,对运动组小鼠进行为期4周的中等强度被动跑台运动干预(10m/min,1h/day)。随后采用Y迷宫和Morris水迷宫分别检测干预后小鼠的工作记忆和空间导航记忆。在行为测试结束后24小时,小鼠麻醉处死,取血液和脑组织。最后采用酶免疫测定(EIA)检测小鼠血清雌激素的含量,Western Blot测定小鼠前额叶皮层和海马中脑源性神经生长因子(BDNF)以及转录因子CREB和p-CREB的表达。研究结果:(1)与SHAM+VEH+SED组小鼠相比,OVX+VEH+SED组小鼠血清雌激素含量显著降低(p0.05);(2)在工作记忆测试中,芳香酶抑制剂注射组(OVX+LET+SED和OVX+LET+EX)小鼠的工作记忆与赋形剂注射组(OVX+VEH+SED和OVX+VEH+EX)小鼠相比并无显著差异(p0.05);(3)在水迷宫获得性训练阶段,芳香酶抑制剂注射组(OVX+LET+SED和OVX+LET+EX)小鼠的空间学习能力与赋形剂注射组(OVX+VEH+SED和OVX+VEH+EX)小鼠相比并无显著差异(p0.05);(4)在空间记忆测试中,芳香酶抑制剂注射组(OVX+LET+SED和OVX+LET+EX)小鼠在目标象限的探索时间显著低于赋形剂注射组(OVX+VEH+SED和OVX+VEH+EX);芳香酶抑制剂注射安静组(OVX+LET+SED)小鼠的平台象限穿梭次数显著低于赋形剂注射组安静(OVX+VEH+SED)小鼠(5)芳香酶抑制剂注射组(OVX+LET+SED和OVX+LET+EX)小鼠海马区的BDNF的表达以及p-CREB/CREB水平均显著低于赋形剂对照组(OVX+VEH+SED和OVX+VEH+EX)(p0.05),而以上蛋白水平在前额叶中没有显著差异(p0.05)。运动对于以上蛋白的表达均无显著影响(p0.05)。研究结论：(1)芳香酶抑制剂对于认知功能的损伤具有脑区特异性:芳香酶抑制剂对小鼠的前额叶依赖的记忆并无显著影响,而对海马相关的记忆的损伤效果较为明显。(2)芳香酶抑制剂对海马相关记忆功能的损伤与海马中BDNF的表达以及CREB磷酸化水平降低有关。(3)4周中等强度的跑台运动未能改善芳香酶抑制剂诱发的小鼠学习记忆功能的损伤。
[Abstract]:Objective: aromatase inhibitors are widely used in the treatment of breast cancer. However, the inhibition of estrogen by aromatase inhibitors leads to the loss of estrogen in the brain of breast cancer patients, which leads to cognitive impairment in patients with breast cancer. The effect of exercise on the improvement of cognitive function has been widely recognized. At the same time, animal studies have confirmed that exercise can repair cognitive damage in ovariectomized rats. However, the effects of exercise on cognitive impairment induced by aromatase inhibitors are rarely reported. The purpose of this study was to establish an animal model of cognitive impairment induced by aromatase inhibitors and to explore the effects of moderate aerobic exercise on cognitive impairment induced by aromatase inhibitors. Methods: the model of mouse menopause was established by ovariectomy. The 3-month-old female C57BL/6 mice were randomly divided into five groups: (1) ovariectomized excipient group (OVX VEH SED); (_ 2) ovariectomized aromatase inhibitor injection quiet group (OVX LET SED); (_ 3) sham-operated excipient group (SHAM VEH SED); (_ 4) ovariectomy Excipient exercise group (OVX VEH EX); (5) Ovariectomized aromatase inhibitor injection exercise group (OVX LET EX). Two weeks after ovariectomy, mice in the aromatase inhibitor injection group were injected intraperitoneally with letrozole (80 渭 g/kg) for 4 weeks to establish a cognitive impairment model. At the same time, the mice in the exercise group were treated with moderate intensity passive treadmill exercise for 4 weeks (10 m / min / min 1 h / day). Then Y maze and Morris water maze were used to detect working memory and spatial navigation memory. 24 hours after the behavioral test, the mice were anesthetized and killed, blood and brain tissue were taken. Finally, the levels of serum estrogen in mice were detected by enzyme immunoassay (EIA) and the expression of brain-derived nerve growth factor (BDNF), transcription factor CREB and p-CREB in prefrontal cortex and hippocampus were detected by Western Blot. The results showed that: (1) compared with SHAM VEH SED group, serum estrogen content in OVX VEH SED group decreased significantly (p0.05); (2) in working memory test. The working memory of (OVX LET SED and OVX LET EX) mice in the aromatase inhibitor injection group was not significantly different from that of the (OVX VEH SED and OVX VEH EX) mice in the excipient injection group (p0.05); (3) at the stage of water maze acquired training. The spatial learning ability of (OVX LET SED and OVX LET EX) mice in the aromatase inhibitor injection group was not significantly different from that of the (OVX VEH SED and OVX VEH EX) mice in the excipient injection group (p0.05); (4). The exploration time in the target quadrant of (OVX LET SED and OVX LET EX) mice in the aromatase inhibitor injection group was significantly lower than the platform quadrant shuttle times in the (OVX VEH SED and OVX VEH EX); aromatase inhibitor injected quiet (OVX LET SED) mice in the excipient injection group. The expression of BDNF and the level of p-CREB/CREB in hippocampus of (OVX LET SED and OVX LET EX) mice in the aromatase inhibitor injection group were significantly lower than those in the excipient control group (OVX VEH SED and OVX VEH EX) (p0.05). There was no significant difference in protein level in prefrontal lobe (p0.05). Exercise had no significant effect on the expression of these proteins (p0.05). Conclusion: (1) aromatase inhibitors have brain region specificity for cognitive impairment: aromatase inhibitors have no significant effect on prefrontal lobe dependent memory in mice. (2) the damage of aromatase inhibitor to hippocampal associated memory function was related to the expression of BDNF and the decrease of CREB phosphorylation level in hippocampus. (3) 4 weeks of moderate treadmill exercise failed. To improve the impairment of learning and memory induced by aromatase inhibitor in mice.
【学位授予单位】：上海体育学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：B842.3

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