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Abstract：
BACKGROUND: EGb 761 is a standardized dry extract of Ginkgo biloba L. leaves traditionally used by Eastern Asia and has been associated with beneficial effects on neurodegeneration disorders, including Alzheimer\'s disease.
OBJECTIVE: Since beneficial interactions between EGb 761 and donepezil have been observed in previous clinical studies, the current study was proposed aiming to further explore related mechanisms from both pharmacokinetics and pharmacodynamics aspects.
METHODS: Pharmacodynamic interactions were studied in scopolamine-induced cognitive impairment rats received two-weeks treatment of vehicle, EGb 761 and/or donepezil by the Morris water maze test and ex vivo evaluation of biomarkers of cholinergic transmission and oxidative stress in rat brain. In the meantime, pharmacokinetic profiles of donepezil and bilobalide were obtained and compared among all treatment groups. In addition, impact of the bioavailable EGb 761 components on donepezil brain penetration was evaluated with the hCMEC/D3 cell monolayer model.
RESULTS: Scopolamine-induced rats with co-treatment of EGb 761 and donepezil had significantly improved cognitive function in the Morris water maze test with increased brain levels of superoxide dismutase and decreased brain levels of acetylcholinesterase and malondialdehyde than that with treatment of only EGb 761 or donepezil. Despite such beneficial pharmacodynamics outcomes, the two-week co-treatment of EGb 761 and donepezil did not alter the plasma pharmacokinetics and brain uptake of donepezil or bilobalide, which was further verified in the hCMEC/D3 monolayer model.
CONCLUSIONS: Co-administration of EGb 761 and donepezil exerted better anti-amnestic effect via further enhanced pro-cholinergic and antioxidative effects of EGb 761 or donepezil in scopolamine-induced cognitive impairment rat without alteration in their systemic/brain exposure.
OBJECTIVE: Since beneficial interactions between EGb 761 and donepezil have been observed in previous clinical studies, the current study was proposed aiming to further explore related mechanisms from both pharmacokinetics and pharmacodynamics aspects.
METHODS: Pharmacodynamic interactions were studied in scopolamine-induced cognitive impairment rats received two-weeks treatment of vehicle, EGb 761 and/or donepezil by the Morris water maze test and ex vivo evaluation of biomarkers of cholinergic transmission and oxidative stress in rat brain. In the meantime, pharmacokinetic profiles of donepezil and bilobalide were obtained and compared among all treatment groups. In addition, impact of the bioavailable EGb 761 components on donepezil brain penetration was evaluated with the hCMEC/D3 cell monolayer model.
RESULTS: Scopolamine-induced rats with co-treatment of EGb 761 and donepezil had significantly improved cognitive function in the Morris water maze test with increased brain levels of superoxide dismutase and decreased brain levels of acetylcholinesterase and malondialdehyde than that with treatment of only EGb 761 or donepezil. Despite such beneficial pharmacodynamics outcomes, the two-week co-treatment of EGb 761 and donepezil did not alter the plasma pharmacokinetics and brain uptake of donepezil or bilobalide, which was further verified in the hCMEC/D3 monolayer model.
CONCLUSIONS: Co-administration of EGb 761 and donepezil exerted better anti-amnestic effect via further enhanced pro-cholinergic and antioxidative effects of EGb 761 or donepezil in scopolamine-induced cognitive impairment rat without alteration in their systemic/brain exposure.
摘要：
背景：EGb761是东亚地区传统使用的银杏叶的标准化干提取物，对神经退行性疾病具有有益作用，包括老年痴呆症.
目的：因为在以前的临床研究中已经观察到EGb761和多奈哌齐之间的有益相互作用，本研究旨在从药代动力学和药效学两方面进一步探讨相关机制。
方法：在东pol碱诱导的认知障碍大鼠中研究了药效学相互作用，通过Morris水迷宫测试和离体评估大鼠脑中胆碱能传递和氧化应激的生物标志物的EGb761和/或多奈哌齐。同时,获得了多奈哌齐和白果内酯的药代动力学曲线，并在所有治疗组之间进行了比较。此外,使用hCMEC/D3细胞单层模型评估了生物可利用EGb761成分对多奈哌齐脑穿透性的影响.
结果：东莨菪碱联合EGb761和多奈哌齐诱导的大鼠在Morris水迷宫试验中的认知功能显著改善，脑内超氧化物歧化酶水平升高，脑内乙酰胆碱酯酶和丙二醛水平降低。尽管有如此有益的药效学结果，EGb761和多奈哌齐的联合治疗2周没有改变多奈哌齐或白果内酯的血浆药代动力学和脑摄取，在hCMEC/D3单层模型中进一步验证。
结论：EGb761和多奈哌齐共同给药通过进一步增强EGb761或多奈哌齐对东莨菪碱诱导的认知功能障碍大鼠的前胆碱能和抗氧化作用发挥更好的抗遗忘作用，而不会改变其全身/脑暴露。
目的：因为在以前的临床研究中已经观察到EGb761和多奈哌齐之间的有益相互作用，本研究旨在从药代动力学和药效学两方面进一步探讨相关机制。
方法：在东pol碱诱导的认知障碍大鼠中研究了药效学相互作用，通过Morris水迷宫测试和离体评估大鼠脑中胆碱能传递和氧化应激的生物标志物的EGb761和/或多奈哌齐。同时,获得了多奈哌齐和白果内酯的药代动力学曲线，并在所有治疗组之间进行了比较。此外,使用hCMEC/D3细胞单层模型评估了生物可利用EGb761成分对多奈哌齐脑穿透性的影响.
结果：东莨菪碱联合EGb761和多奈哌齐诱导的大鼠在Morris水迷宫试验中的认知功能显著改善，脑内超氧化物歧化酶水平升高，脑内乙酰胆碱酯酶和丙二醛水平降低。尽管有如此有益的药效学结果，EGb761和多奈哌齐的联合治疗2周没有改变多奈哌齐或白果内酯的血浆药代动力学和脑摄取，在hCMEC/D3单层模型中进一步验证。
结论：EGb761和多奈哌齐共同给药通过进一步增强EGb761或多奈哌齐对东莨菪碱诱导的认知功能障碍大鼠的前胆碱能和抗氧化作用发挥更好的抗遗忘作用，而不会改变其全身/脑暴露。
