title: Probucol plus cilostazol attenuate hypercholesterolemia‑induced exacerbation in ischemic brain injury via anti-inflammatory effects.
abstract: Probucol, a lipid-lowering agent with anti-oxidant properties, is involved in protection against atherosclerosis, while cilostazol, an antiplatelet agent, has diverse neuroprotective properties. In this study, we investigated the anti-inflammatory effects of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet (HFD) with or without 0.3% probucol and/or 0.2% cilostazol for 10 weeks. To assess the protective effects of the combined therapy of probucol and cilostazol on ischemic injury, the mice received 40 min of middle cerebral artery occlusion (MCAO). Infarct volumes, neurobehavioral deficits and neuroinflammatory mediators were subsequently evaluated 48 h after reperfusion. Probucol alone and probucol plus cilostazol significantly decreased total- and low-density lipoprotein (LDL)-cholesterol in ApoE KO with HFD. MCAO resulted in significantly larger infarct volumes in ApoE KO mice provided with HFD compared to those fed a regular diet, although these volumes were significantly reduced in the probucol plus cilostazol group. Consistent with a smaller infarct size, probucol alone and the combined treatment of probucol and cilostazol improved neurological and motor function. In addition, probucol alone and probucol plus cilostazol decreased MCP-1 expression and CD11b and GFAP immuno-reactivity in the ischemic cortex. These findings suggested that the inhibitory effects of probucol plus cilostazol in MCP-1 expression in the ischemic brain with hypercholesterolemia allowed the identification of one of the mechanisms responsible for anti-inflammatory action. Probucol plus cilostazol may therefore serve as a therapeutic strategy for reducing the impact of stroke in hypercholesterolemic subjects.
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.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Yong-Il
authors.initials: YI
authors.lastname: Shin
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Byung Tae
authors.initials: BT
authors.lastname: Choi
authors.affiliation: Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D039481:CD11b Antigen / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D000077407:Cilostazol; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011341:Probucol / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D013777:Tetrazoles; D000077407:Cilostazol; D011341:Probucol