Objective To investigate the effect of estrogen replacement therapy applied in different periods to ovariectomized rats and to evaluate the cognitive function of the rats.Methods Totally 40 rats were ovariectomized to be postmenopausal models.They were divided into early hormone replacement therapy group (n =10,managed by estradiol valerate at day 3 after surgery),early control group (n =10,managed by saline at day 3 after surgery),late hormone replacement therapy (n =10,managed by estradiol valerate at day 90 after surgery for 30 days) and late control group (n =10,managed by saline at day 90 after surgery for 30 days).The behavior indicators of the rats were evaluated by Morris watermaze and hippocampal metabolite was detected by proton magnetic resonance spectroscopy,including N-acetylaspartate (NAA),choline containing compounds (Cho),creatine(Cr),myoinositol (mI),NAA/Cr,Cho/Cr and mI/Cr.Results (1) Navigation test: escape latency were (43 ± 13) s at the early control group,(28 ± 9) s at the early HRT group,(82 ±26) s at the late control group and (48 ± 18) s at late HRT group.Swimming distance were (1 404 ± 238) cm at the early control group,(878 ± 354) cm at the early HRT group,(2411 ±818) cm at the late control group and (1 310 ±434) cm at the late HRT group.The escape latency and swimming distance of the early and late HRT groups were significantly shorter than those at the control groups (P ＜ 0.05).(2) Spatial probe test: the swimming time in the target quadrant of rats in the early HRT group (34.0 ± 3.0) s were longer than those in other groups (P ＜ 0.05).(3) Proton magnetic resonance spectroscopy: NAA/Cr were 1.12 ±0.17 at the early control group,1.26 ±0.12 at the early HRT group,1.57 ±0.21 at the late control group and 1.38 ±0.28 at the late HRT group.The late HRT group and the late control group were higher than their early groups (F =6.05,P =0.040).There was no significant difference between the HRT groups and the control groups (F =0.04,P =0.860).mI/Cr were 0.69 ±0.04 at the early control group,0.46 ±0.12 at the early HRT group,0.70 ±0.03 at the late control group and 0.75 ± 0.08 at the late HRT group.There were statistically significant differences of the experimental time between the early and late groups(F =16.45,P =0.004).The differences between the early HRT group and the early control group,and the late HRT group and the late control group were significant(F =6.01,P =0.040).And there was an interaction with the experimental time and HRT measures (F =13.79,P =0.006) ; early HRT can reduce the average level of mI/Cr.Cho/Cr were 0.95 ± 0.09 at the early control group,0.80 ±0.12 at the early HRT group,0.87 ±0.09 at the late control group and 0.85 ± 0.12 at the late HRT group.There was no significant difference among those groups (P ＞0.05).NAA/mI: there was an interaction with the experimental time and HRT measures (F =12.95,P =0.007).Early HRT can elevated levels of NAA/mI,while the late results were reversed.Conclusion Earlier estrogen replacement therapy may play a positive role in improving cognitive function of the ovariectomized rats.%目的 观察雌激素补充时机对绝经模型大鼠空间学习和记忆力的影响,为绝经后雌激素补充时机的选择提供动物实验依据.方法 将40只SD大鼠行双侧卵巢切除术,建立绝经模型.术后将模型大鼠计算机随机分为早期激素补充治疗(HRT)组(n=10,术后3d予戊酸雌二醇补充治疗30 d)、早期对照组(n=10,术后3d予生理盐水30 d)、晚期HRT组(n=10,术后90 d予戊酸雌二醇补充治疗30 d)、晚期对照组(n=10,术后90 d予生理盐水30 d).对40只大鼠行Morris水迷宫实验测定行为学指标；并行MRI质子波谱成像技术扫描检测海马神经元代谢产物相关数据,包括N-乙酰基天冬氨酸(NAA)、胆碱化合物(Cho)、肌酸复合物(Cr)、肌醇(mI),并以Cr值为标准,计算NAA/Cr、Cho/Cr、mI/Cr、NAA/mI比值.结果 (1)Morris水迷宫定位航行实验中,逃避潜伏期:早期对照组为(43±13)s,早期HRT组为(28 ±9)s,晚期对照组为(82±26)s,晚期HRT组为(48±18)s;游泳行程:早期对照组(1 404 ±238)cm,早期HRT组(878±354)cm,晚期对照组(2 411±818)cm,晚期HRT组(1 310±434)cm；绝经模型大鼠早、晚期HRT组的逃避潜伏期及游泳行程明显较早、晚期对照组短(P＜0.01).(2) Morris水迷宫空间探索实验:早期HRT组在目标象限游泳停留时间为(34.0±3.0)s,较其他各组时间长(P＜0.05).(3) MRI质子波谱成像技术检测结果:NAA/Cr:早期对照组为1.12±0.17,早期HRT组1.26±0.12,晚期对照组1.57±0.21,晚期HRT组1.38±0.28,晚期HRT组和晚期对照组的NAA/Cr高于早期HRT组和早期对照组(F=6.05,P=0.040)；早期HRT组与早期对照组、晚期HRT组与晚期对照组比较,差异无统计学意义(F=0.04,P=0.860).mI/Cr:早期对照组0.69±0.04,早期HRT组0.46±0.12,晚期对照组0.70±0.03,晚期HRT组0.75±0.08,晚期HRT组、晚期对照组与早期HRT组、早期对照组比较,差异有统计学意义(F=16.45,P=0.004),其中早期HRT组与早期对照组、晚期HRT组与晚期对照组组间差异明显(F =6.01,P=0.040),且实验干预的起始时间与是否HRT干预对mI/Cr存在交互作用(F=13.79,P=0.006),即早期HRT可使mI/Cr比值降低.Cho/Cr:早期对照组0.95±0.09,早期HRT组0.80±0.12,晚期对照组0.87±0.09,晚期HRT组0.85±0.12,各组绝经模型大鼠与神经细胞膜稳态有关的Cho均无明显变化,各组间比较,差异无统计学意义(P＞0.05).NAA/mI:实验干预的起始时间与是否HRT干预对NAA/mI存在交互作用(F=12.95,P=0.007),早期HRT可使NAA/mI比值升高,而晚期结果则相反.结论 HRT早期干预对改善绝经模型大鼠的空间学习和记忆力有积极作用.
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