Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
J Pharmacol Exp Ther. 2011 Aug;338(2):451-7. doi: 10.1124/jpet.111.181180. Epub 2011 May 5.
Hypercholesterolemia may increase stroke risk by accelerating atherosclerosis, narrowing the luminal diameter in cerebral vessels, and disrupting both vascular endothelial and smooth muscle function. In the present study, we investigated the beneficial effects of combinatorial therapy with probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet with or without 0.5% probucol and/or 0.2% cilostazol for 10 weeks. Probucol alone and probucol and cilostazol significantly decreased total, low-density lipoprotein, and high-density lipoprotein cholesterol, whereas cilostazol did not affect the plasma cholesterol levels in ApoE KO mice. Administration of probucol alone and cilostazol alone significantly decreased atherosclerotic lesion area in the aorta, with a significant decrease evident using combinatorial administration. Middle cerebral artery occlusion resulted in significantly larger infarct volumes in ApoE KO mice fed 10 weeks of high-fat diet compared with those in ApoE KO mice fed a regular diet. The infarct volume was reduced significantly using probucol alone or cilostazol alone and even was reduced significantly by their combinatorial administration. Consistent with a larger infarct size, the combinatorial therapy prominently improved neurological function. The combinatorial administration increased cerebral blood flow during ischemia. Expression of endothelial nitric oxide synthase and adiponectin in the cortex were decreased by high-fat diet but were elevated by combinatorial treatment. Adiponectin expression colocalized within the cerebral vascular endothelium. The data suggest that the combination of probucol and cilostazol prevents cerebrovascular damage in focal cerebral ischemic mice with hypercholesterolemia by up-regulation of endothelial nitric oxide synthase and adiponectin.
高胆固醇血症可通过加速动脉粥样硬化、缩小脑血管管腔直径以及破坏血管内皮和平滑肌功能，从而增加中风风险。在本研究中，我们研究了普罗布考与西洛他唑联合治疗高胆固醇血症局灶性脑缺血的有益作用。载脂蛋白 E（ApoE）敲除（KO）小鼠给予高脂饮食，或同时给予 0.5%普罗布考和/或 0.2%西洛他唑，共 10 周。普罗布考单独及与西洛他唑联合应用可显著降低总胆固醇、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇，而西洛他唑对 ApoE KO 小鼠的血浆胆固醇水平无影响。普罗布考单独及与西洛他唑联合应用均可显著降低主动脉粥样硬化病变面积，联合应用时降低更为显著。与给予常规饮食的 ApoE KO 小鼠相比，给予 10 周高脂饮食的 ApoE KO 小鼠大脑中动脉闭塞导致梗死体积显著增大。普罗布考单独或西洛他唑单独应用可显著减小梗死体积，联合应用时效果更显著。与梗死体积较大相一致，联合治疗可显著改善神经功能。联合治疗可增加缺血期间的脑血流。皮质中内皮型一氧化氮合酶和脂联素的表达因高脂饮食而降低，但经联合治疗后升高。脂联素的表达与脑血管内皮内共定位。这些数据表明，普罗布考与西洛他唑联合应用可通过上调内皮型一氧化氮合酶和脂联素，预防高胆固醇血症局灶性脑缺血小鼠的脑血管损伤。
