University of Pittsburgh School of Pharmacy, 1004 Salk Hall, Pittsburgh, PA 15261, USA.
Horm Behav. 2011 Apr;59(4):503-11. doi: 10.1016/j.yhbeh.2011.01.011. Epub 2011 Feb 3.
Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3mg/kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don+E2 significantly enhanced acquisition of the task in rats with partial lesions (<50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don+E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease.
雌激素治疗对认知表现的影响似乎随着年龄的增长和卵巢功能丧失后时间的推移而减弱。我们假设这是由于基底前脑胆碱能功能的降低，而使用胆碱能增强剂可以逆转这种影响。本研究测试了是否将胆碱酯酶抑制剂多奈哌齐与雌二醇治疗相结合，可以增强/恢复选择性隔区胆碱能神经元损伤的年轻去卵巢大鼠中雌二醇对认知表现的影响。192IgG-细胞松弛素直接注入内侧隔核以产生选择性胆碱能损伤。然后，大鼠接受多奈哌齐（Don，每天腹腔注射 3mg/kg/天）或载体，然后接受 17β-雌二醇（E2，通过皮下植入的硅酮胶囊给药）或空胶囊。大鼠接受延迟匹配位置（DMP）T 迷宫任务的训练，先前的研究表明该任务对去卵巢和雌激素替代敏感。结果表明，单独使用雌二醇或多奈哌齐均不能显著增强胆碱能损伤大鼠对 DMP 任务的获得。然而，联合治疗是有效的，这取决于损伤的严重程度。Don+E2 显著增强了部分损伤（<50%胆碱能神经元丢失）大鼠对任务的获得，但不能增强严重损伤的大鼠。这种效果主要归因于刻板行为的减少。Don+E2 还改善了部分损伤大鼠的工作记忆，因为与对照组相比，在增加的试验间延迟期间，大鼠的表现明显更好。这些发现表明，即使是部分隔区胆碱能神经元的丢失也会降低雌激素治疗对认知表现的影响，并表明将胆碱酯酶抑制剂与雌激素治疗相结合可以帮助恢复对性能的有益影响。我们提出，联合治疗可能对女性具有类似的有益效果，特别是对那些多年未使用雌激素治疗且开始出现认知障碍或早期阿尔茨海默病迹象的老年女性。
