Donepezil (E2020)

Donepezil (E2020) is an acetylcholinesterase (AChE) inhibitor with an IC₅₀ of 6.7nM^[1]. Donepezil (E2020) can block MAPK and NF-κB signaling, directly inhibit AβO-induced microglial activation, and help improve neurodegenerative memory impairment ^[2].

In vitro, Donepezil (E2020) (10 μM) treated rat primary cortical cells for 24 hours, which induced an increase in SNX33 mRNA expression in the cells, and the Aβ40 level in the culture medium was significantly reduced in a concentration- and timedependent manner^[3]. Donepezil (E2020) (0.1-10μM) dose-dependently reduces glutamate toxicity-induced retinal ganglion cell death^[4]. Donepezil (E2020) (1-10μM) can protect HUVECs from hydrogen peroxide-induced cell damage, significantly upregulating the expression of HIF-1α and MnSOD in the cells, and may also have a similar protective effect on ischemic tissue^[5].

In vivo, Donepezil (E2020) (1.5mg/kg) was administered orally twice a day for 21 days, significantly increasing ACh levels in the cortex of aged rats, with ACh release increasing by 210% ^[6]. Donepezil (E2020), injected intraperitoneally in rats, dose-dependently caused an increase in salivation and tremor, which are obvious signs of cholinergic behavior, with an ED₅₀ of 6 μmol/kg^[7].

References:

[1] Ramón Cacabelos. Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics[J]. Neuropsychiatric Disease & Treatment, 2007, 3(3): 303-333.

[2] Kim H G , Moon M , Choi J G ,et al.Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo.[J].Neurotoxicology, 2014, 40:23-32.

[3] Takada-Takatori Y , Nakagawa S , Kimata R ,et al. Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons[J]. Scientific Reports, 2019.

[4] Miki A, Otori Y, et al. Protective effect of donepezil on retinal ganglion cells in vitro and in vivo[J]. Curr Eye Res. 2006, 31(1):69-77.

[5] Huang Z H , Guo W , Zhang L L ,et al.Donepezil Protects Endothelial Cells against Hydrogen Peroxide‐Induced Cell Injury[J]. Cns Neuroscience & Therapeutics, 2012, 18(2):185-187.

[6] Scali C , Casamenti F , Bellucci A ,et al. Effect of subchronic administration of metrifonate, rivastigmine and donepezil on brain acetylcholine in aged F344 rats[J]. Journal of Neural Transmission, 2002, 109(7-8):1067-1080.

[7]Snape, M.F., et al., A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066. Neuropharmacology, 1999. 38(1):181-93.

Donepezil (E2020)是一种乙酰胆碱酯酶（AChE）抑制剂，IC₅₀为6.7nM^[1]。Donepezil (E2020)能阻断MAPK和NF-κB信号，直接抑制AβO诱导的小胶质细胞活化，有助于改善神经退行性记忆障碍^[2]。

在体外，Donepezil (E2020)（10μM）处理大鼠原代皮质细胞24h，诱导了细胞中SNX33 mRNA表达增加，且培养基中的Aβ40水平以浓度和时间依赖性方式显著降低^[3]。Donepezil (E2020)（0.1-10μM）剂量依赖性地减少了谷氨酸毒性引起的视网膜神经节细胞死亡^[4]。Donepezil (E2020)（1-10μM）可以保护过氧化氢诱导的HUVECs细胞损伤，显著上调了细胞中HIF-1α和MnSOD的表达，也可能对缺血组织具有类似的保护作用^[5]。

在体内，Donepezil (E2020)（1.5mg/kg）一天两次连续口服给药21天，显著升高了老年大鼠皮层中的ACh水平，ACh释放量增加了210%^[6]。Donepezil (E2020)在大鼠腹膜内注射，剂量依赖性地导致唾液分泌和震颤的增加，是明显的胆碱能行为体征，ED₅₀为6μmol / kg^[7]。