School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China.
J Ethnopharmacol. 2021 Apr 6;269:113711. doi: 10.1016/j.jep.2020.113711. Epub 2020 Dec 25.
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.
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.
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.
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.
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.
银杏叶提取物 761 是银杏叶的一种标准化干提取物，传统上在东亚被使用，并与对神经退行性疾病（包括阿尔茨海默病）的有益作用有关。
由于在以前的临床研究中观察到银杏叶提取物 761 和多奈哌齐之间存在有益的相互作用，因此提出了本研究，旨在从药代动力学和药效学两个方面进一步探索相关机制。
通过 Morris 水迷宫试验研究了在东莨菪碱诱导的认知障碍大鼠中，在接受 2 周的载体、银杏叶提取物 761 和/或多奈哌齐治疗后，观察药物的药效学相互作用，并在大鼠大脑中评估胆碱能传递和氧化应激的生物标志物的体外评估。同时，获得了多奈哌齐和白果内酯在所有治疗组中的药代动力学特征，并进行了比较。此外，还使用 hCMEC/D3 细胞单层模型评估了生物利用的银杏叶提取物 761 成分对多奈哌齐脑穿透的影响。
与单独使用银杏叶提取物 761 或多奈哌齐相比，银杏叶提取物 761 和多奈哌齐联合治疗的东莨菪碱诱导的大鼠在 Morris 水迷宫试验中认知功能显著改善，大脑中超氧化物歧化酶水平升高，乙酰胆碱酯酶和丙二醛水平降低。尽管药效学结果如此有益，但银杏叶提取物 761 和多奈哌齐联合治疗 2 周并未改变多奈哌齐或白果内酯的血浆药代动力学和脑摄取，这在 hCMEC/D3 单层模型中得到了进一步验证。
银杏叶提取物 761 和多奈哌齐联合给药通过进一步增强银杏叶提取物 761 或多奈哌齐的促胆碱能和抗氧化作用，在东莨菪碱诱导的认知障碍大鼠中发挥更好的抗健忘作用，而不改变其全身/脑暴露。
