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Research ArticleCardiovascular

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Ji Hyun Kim, Sun Haeng Park, Sun Sik Bae, Ki Whan Hong, Yong Deok Kim, Kyung Pil Park, Byung Tae Choi and Hwa Kyoung Shin
Journal of Pharmacology and Experimental Therapeutics August 2011, 338 (2) 451-457; DOI: https://doi.org/10.1124/jpet.111.181180
Ji Hyun Kim
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Sun Haeng Park
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Sun Sik Bae
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Ki Whan Hong
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Yong Deok Kim
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Kyung Pil Park
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Byung Tae Choi
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Hwa Kyoung Shin
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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.

Footnotes

  • This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology [Grants 2009-0066654, 2010-0007470]; and Otsuka Pharmaceutical (Tokushima, Japan).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181180.

  • ABBREVIATIONS:

    NO
    nitric oxide
    ApoE
    apolipoprotein E
    CBF
    cerebral blood flow
    eNOS
    endothelial nitric-oxide synthase
    HFD
    high-fat diet
    KO
    knockout
    LDL
    low-density lipoprotein
    MCA
    middle cerebral artery
    PBS
    phosphate-buffered saline.

  • Received March 2, 2011.
  • Accepted May 4, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 2
1 Aug 2011
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Research ArticleCardiovascular

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Ji Hyun Kim, Sun Haeng Park, Sun Sik Bae, Ki Whan Hong, Yong Deok Kim, Kyung Pil Park, Byung Tae Choi and Hwa Kyoung Shin
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 451-457; DOI: https://doi.org/10.1124/jpet.111.181180

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Research ArticleCardiovascular

Combinatorial Effect of Probucol and Cilostazol in Focal Ischemic Mice with Hypercholesterolemia

Ji Hyun Kim, Sun Haeng Park, Sun Sik Bae, Ki Whan Hong, Yong Deok Kim, Kyung Pil Park, Byung Tae Choi and Hwa Kyoung Shin
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 451-457; DOI: https://doi.org/10.1124/jpet.111.181180
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