Department of Color Ultrasonic, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China.
Department of Color Ultrasonic, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China.
Eur J Pharmacol. 2017 Sep 15;811:60-65. doi: 10.1016/j.ejphar.2017.05.053. Epub 2017 May 30.
The endothelium lines the interior surface of blood vessels, and under pathophysiologic conditions, its integrity can be compromised due to a disturbance in the expression of tight junctions. Donepezil is a licensed drug used in the palliative treatment of Alzheimer's disease (AD). Increasing evidence has reported that donepezil has an anti-inflammatory activity. However, little information is available regarding the role of donepezil in vascular diseases. In this study, we found that pretreatment with donepezil significantly ameliorated endothelial permeability induced by tumor necrosis factor (TNF-α) by restoring the expression of the tight junction proteins vascular endothelial cadherin (VE-cadherin) and zonula occludens-1 (ZO-1) in human umbilical vein endothelial cells (HUVECs). Mechanistically, our results indicate that donepezil regulates the expression and activity of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1), but not matrix metalloproteinase-2 (MMP-2) or tissue inhibitor of metalloproteinases 2 (TIMP-2). Importantly, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/ serine-threonine kinase (AKT)/ nuclear factor kappa B (NF-κB) pathway was found to be involved in this process. These results suggest that donepezil may potentially play an important therapeutic role in vascular diseases.
内皮细胞排列在血管的内表面，在病理生理条件下，由于紧密连接表达的紊乱，其完整性可能受到损害。多奈哌齐是一种用于阿尔茨海默病（AD）姑息治疗的许可药物。越来越多的证据表明，多奈哌齐具有抗炎活性。然而，关于多奈哌齐在血管疾病中的作用的信息很少。在这项研究中，我们发现多奈哌齐预处理可通过恢复人脐静脉内皮细胞（HUVEC）中紧密连接蛋白血管内皮钙黏蛋白（VE-cadherin）和封闭蛋白-1（ZO-1）的表达，显著改善肿瘤坏死因子（TNF-α）诱导的内皮通透性。从机制上讲，我们的结果表明，多奈哌齐调节基质金属蛋白酶-9（MMP-9）和基质金属蛋白酶抑制剂 1（TIMP-1）的表达和活性，但不调节基质金属蛋白酶-2（MMP-2）或基质金属蛋白酶抑制剂 2（TIMP-2）。重要的是，发现磷脂酰肌醇-4,5-二磷酸 3-激酶（PI3K）/丝氨酸-苏氨酸激酶（AKT）/核因子 kappa B（NF-κB）途径参与了这一过程。这些结果表明，多奈哌齐可能在血管疾病中发挥重要的治疗作用。
