Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.
Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.
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DOI：
10.1016/j.yhbeh.2011.01.011
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发表时间：
2011-04
影响因子：
3.5
通讯作者：
Nelson, D.
中科院分区：
文献类型：
--
作者：
Gibbs, R. B.;Chipman, A. M.;Nelson, D.
关键词：
雌激素治疗对认知能力的影响似乎随着年龄和卵巢功能丧失后的时间而减少。我们推测这是由于基底前脑胆碱能功能的减少，用胆碱能增强剂治疗可以逆转这种作用。本研究测试了是否结合胆碱酯酶抑制剂多奈哌齐与雌二醇治疗可以增强/恢复雌二醇对年轻的卵巢切除大鼠的隔胆碱能神经元的选择性病变的认知性能的影响。将192 IgG-皂草素直接注射到内侧隔中以产生选择性胆碱能损伤。然后用多奈哌齐（Don，每天注射3 mg/Kg/天，i. p.）或载体，然后与17β-雌二醇（E2，通过硅橡胶胶囊植入s.c.）或者是空胶囊大鼠进行延迟匹配定位（delayed matching to position，T-maze）任务训练，先前的研究表明，T-maze任务对卵巢切除术和雌激素替代敏感。结果表明，无论是雌二醇或多奈哌齐单独显着增强收购的胆碱能损伤大鼠的任务。然而，联合治疗是有效的，这取决于病变的严重程度。Don+E2显著增强部分损伤大鼠（胆碱能神经元损失<50%）的任务获得，但在严重损伤大鼠中没有。这种效果主要是由于持续行为的减少。Don+E2还改善了部分病变大鼠的工作记忆，在增加的试验间延迟期间，其表现明显优于对照组。这些研究结果表明，即使部分损失隔胆碱能神经元可以减少雌激素治疗对认知性能的影响，并证明胆碱酯酶抑制剂与雌激素治疗相结合，可以帮助恢复有益的性能。我们认为，联合治疗可能对女性有类似的有益效果，特别是对多年未使用雌激素治疗并开始出现认知障碍或早期阿尔茨海默病迹象的老年女性。
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 3 mg/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.
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