Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats
Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats
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DOI：
10.1016/s0014-2999(99)00545-2
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发表时间：
1999-09-10
影响因子：
5
通讯作者：
Yamanishi, Y
中科院分区：
文献类型：
--
作者：
Kosasa, T;Kuriya, Y;Yamanishi, Y
口服中枢作用乙酰胆碱酯酶（AChE）抑制剂、盐酸多奈哌齐（多奈哌齐：E2020：（+/-）-2-[（1-苄基哌啶-4-基）甲基]-5,6-二甲氧基-茚满-1-一盐酸盐）、他克林的效果 （9-氨基-1,2,3,4-四氢吖啶盐酸盐）和ENA-713（卡巴拉汀：(S)-N-乙基-3-[(1-二甲基-氨基)乙基]-N-甲基-苯基氨基甲酸酯酒石酸氢盐），已开发用于治疗阿尔茨海默病，在细胞外 采用微透析技术，在灌注液中不添加胆碱酯酶抑制剂，测定大鼠海马乙酰胆碱浓度。我们还比较了这些药物对脑 AChE 的抑制作用和脑浓度。 2.5 mg/kg 多奈哌齐和 5 mg/kg 他克林显示出显着效果，持续时间超过 6 小时。在这些剂量下，在施用多奈哌齐后约1.5小时和施用他克林后约2小时观察到最大增加，分别为前水平的499%和422%。 ENA-713在0.625、1.25和2.5 mg/kg剂量下产生显着效果，分别持续约1、2和4小时。这些剂量在给药后约0.5小时产生的最大增加分别为预水平的190%、346%和458%。 2.5 mg/kg多奈哌齐、10 mg/kg他克林和2.5 mg/kg ENA-713抑制脑AChE的时程是相同剂量下细胞外乙酰胆碱增加作用的镜像。口服2.5 mg/kg多奈哌齐和10 mg/kg他克林后脑内药物浓度时程与相同剂量下脑AChE抑制作用一致，且各参数之间呈线性关系。 ENA-713 的脑浓度为 2.5 mg/kg，在所有测量时间点均低于定量限。这些结果表明，口服多奈哌齐、他克林和ENA-713主要通过抑制AChE来增加海马突触间隙中的乙酰胆碱浓度，并且多奈哌齐对中枢胆碱能系统的活性比他克林更强，比ENA-713更持久。 (C) 1999 Elsevier Science B.V. 保留所有权利。
The effects of oral administration of the centrally acting acetylcholinesterase (AChE) inhibitors, donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride), tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and ENA-713 (rivastigmine: (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate), which have been developed for the treatment of Alzheimer's disease, on the extracellular acetylcholine concentration in the hippocampus of rats were evaluated by using a microdialysis technique without adding cholinesterase inhibitor to the perfusion solution. We also compared the inhibition of brain AChE and the brain concentrations of these drugs. Donepezil at 2.5 mg/kg and tacrine at 5 mg/kg showed significant effects for more than 6 h. At these doses, the maximum increases were observed at about 1.5 h after administration of donepezil, and at about 2 h with tacrine, and were 499% and 422% of the pre-level, respectively. ENA-713 produced significant effects at doses of 0.625, 1.25 and 2.5 mg/kg, which lasted for about 1, 2 and 4 h, respectively. The maximum increases produced by these doses at about 0.5 h after administration were 190, 346 and 458% of the pre-level, respectively. The time courses of brain AChE inhibition with donepezil at 2.5 mg/kg, tacrine at 10 mg/kg and ENA-713 at 2.5 mg/kg were mirror images of the extracellular acetylcholine-increasing action at the same doses. The time courses of the brain concentrations of drugs after oral administration of donepezil at 2.5 mg/kg and tacrine at 10 mg/kg were consistent with those of brain AChE inhibition at the same doses, and there was a linear relation between these parameters. Brain concentration of ENA-713 at 2.5 mg/kg was below the limit of quantification at all time points measured. These results suggest that oral administration of donepezil, tacrine and ENA-713 increases acetylcholine concentration in the synaptic cleft of the hippocampus mostly through AChE inhibition, and that donepezil has a more potent activity than tacrine and a longer-lasting effect than ENA-713 on the central cholinergic system. (C) 1999 Elsevier Science B.V. All rights reserved.