Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala (Punjab) 147002, India.
Korean J Physiol Pharmacol. 2014 Jun;18(3):201-9. doi: 10.4196/kjpp.2014.18.3.201. Epub 2014 Jun 12.
The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5(th) to 8(th) week of L-methionine treatment). On 52(nd) day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.
本研究旨在探讨选择性 ETA 受体拮抗剂安贝生坦对高同型半胱氨酸血症诱导的实验性血管性痴呆的疗效。给予 L-蛋氨酸 8 周以诱导雄性大鼠高同型半胱氨酸血症和相关的血管性痴呆。安贝生坦给予 L-蛋氨酸处理的效应大鼠 4 周（从第 5 周到第 8 周给予 L-蛋氨酸治疗）。第 52 天，动物开始暴露于 Morris 水迷宫（MWM）中，以测试其学习和记忆能力。还测量了血管内皮功能、血清硝酸盐/亚硝酸盐水平、脑硫代巴比妥酸反应性物质（TBARS）、脑还原型谷胱甘肽（GSH）水平和脑乙酰胆碱酯酶（AChE）活性。L-蛋氨酸处理的动物表现出明显的学习和记忆障碍、内皮功能障碍、血清硝酸盐/亚硝酸盐和脑 GSH 水平降低以及脑 TBARS 水平和 AChE 活性升高。安贝生坦显著改善了高同型半胱氨酸血症引起的学习、记忆、内皮功能障碍和各种生化参数的变化。这些作用与阳性对照多奈哌齐相当。结论是，选择性 ETA 受体拮抗剂安贝生坦可被视为治疗高同型半胱氨酸血症诱导的血管性痴呆的潜在药物。
