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 of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. 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 + cilostazol significantly decreased total-, low density lipoprotein- and high density lipoprotein-cholesterol, while 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 the combinatorial administration. Middle cerebral artery occlusion resulted in significantly larger infarct volumes in ApoE KO with 10 weeks of high-fat diet compared to ApoE KO fed a regular diet. The infarct volume was significantly reduced using probucol alone or cilostazol alone and was even significantly reduced 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 the high-fat diet, which were elevated by the combinatorial treatment. Adiponectin expression colocalized within the cerebral vascular endothelium. The data suggests that the combination of probucol and cilostazol prevent cerebrovascular damage in focal cerebral ischemic mice with hypercholesterolemia by up-regulation of endothelial nitric oxide synthase and adiponectin.
- Received March 2, 2011.
- Revision received May 3, 2011.
- Accepted May 4, 2011.
- The American Society for Pharmacology and Experimental Therapeutics