title: Combinatorial effect of probucol and cilostazol in focal ischemic mice with hypercholesterolemia.
abstract: 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.
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Sun Haeng
authors.initials: SH
authors.lastname: Park
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.forename: Yong Deok
authors.initials: YD
authors.lastname: Kim
authors.forename: Kyung Pil
authors.initials: KP
authors.lastname: Park
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D000077407:Cilostazol; D004359:Drug Therapy, Combination; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011341:Probucol / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D013777:Tetrazoles; D000077407:Cilostazol; D011341:Probucol