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Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding.

Abstract

Dysfunction of the blood-brain barrier (BBB) is an early pathological feature of vascular dementia and Alzheimer's disease (AD) and is triggered by inflammatory stimuli. Probucol is a lipid-lowering agent with potent anti-oxidant properties once commonly used for the treatment of cardiovascular disease. Probucol therapy was found to stabilize cognitive symptoms in elderly AD patients, whereas in amyloid transgenic mice probucol was shown to attenuate amyloidosis. However, the mechanisms underlying the effects of probucol have note been determined. In the present study we investigated whether probucol can prevent BBB disturbances induced by chronic ingestion of proinflammatory diets enriched with either 20% (w/w) saturated fats (SFA) or 1% (w/w) cholesterol. Mice were fed the diets for 12 weeks before they were killed and BBB integrity was measured. Mice maintained on either the SFA- or cholesterol-supplemented diets were found to have a 30- and sevenfold greater likelihood of BBB dysfunction, respectively, as determined by the parenchymal extravasation of plasma-derived immunoglobulins and endogenous lipoprotein enrichment with β-amyloid. In contrast, mice fed the SFA- or cholesterol-enriched diets that also contained 1% (w/w) probucol showed no evidence of BBB disturbance. The parenchymal expression of glial fibrillary acidic protein, a marker of cerebrovascular inflammation, was significantly greater in mice fed the SFA-enriched diet. Plasma lipid, β-amyloid and apolipoprotein B levels were not increased by feeding of the SFA- or cholesterol-enriched diets. However, mice fed the SFA- or cholesterol-enriched diets did exhibit increased plasma non-esterified fatty acid levels that were not reduced by probucol. The data suggest that probucol prevents disturbances of BBB induced by chronic ingestion of diets enriched in SFA or cholesterol by suppressing inflammatory pathways rather than by modulating plasma lipid homeostasis.

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  • Authors+Show Affiliations

    ,

    Faculty of Health Sciences, School of Public Health, Curtin Health Innovation Research Institute Biosciences Research Precinct, Curtin University, Bentley, WA, Australia.

    , , , ,

    Source

    MeSH

    Amyloid beta-Peptides
    Animals
    Apolipoproteins B
    Blood-Brain Barrier
    Cerebrovascular Disorders
    Cholesterol, Dietary
    Diet
    Dietary Fats
    Fatty Acids
    Female
    Glial Fibrillary Acidic Protein
    Hypolipidemic Agents
    Immunoglobulins
    Inflammation
    Lipoproteins
    Mice
    Mice, Inbred C57BL
    Probucol
    Random Allocation

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    23167559

    Citation

    Takechi, Ryusuke, et al. "Probucol Prevents Blood-brain Barrier Dysfunction in Wild-type Mice Induced By Saturated Fat or Cholesterol Feeding." Clinical and Experimental Pharmacology & Physiology, vol. 40, no. 1, 2013, pp. 45-52.
    Takechi R, Galloway S, Pallebage-Gamarallage MM, et al. Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding. Clin Exp Pharmacol Physiol. 2013;40(1):45-52.
    Takechi, R., Galloway, S., Pallebage-Gamarallage, M. M., Lam, V., Dhaliwal, S. S., & Mamo, J. C. (2013). Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding. Clinical and Experimental Pharmacology & Physiology, 40(1), pp. 45-52. doi:10.1111/1440-1681.12032.
    Takechi R, et al. Probucol Prevents Blood-brain Barrier Dysfunction in Wild-type Mice Induced By Saturated Fat or Cholesterol Feeding. Clin Exp Pharmacol Physiol. 2013;40(1):45-52. PubMed PMID: 23167559.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding. AU - Takechi,Ryusuke, AU - Galloway,Susan, AU - Pallebage-Gamarallage,Menuka M, AU - Lam,Virginie, AU - Dhaliwal,Satvinder S, AU - Mamo,John C, PY - 2012/07/10/received PY - 2012/10/24/revised PY - 2012/11/15/accepted PY - 2012/11/22/entrez PY - 2012/11/22/pubmed PY - 2013/9/4/medline SP - 45 EP - 52 JF - Clinical and experimental pharmacology & physiology JO - Clin. Exp. Pharmacol. Physiol. VL - 40 IS - 1 N2 - Dysfunction of the blood-brain barrier (BBB) is an early pathological feature of vascular dementia and Alzheimer's disease (AD) and is triggered by inflammatory stimuli. Probucol is a lipid-lowering agent with potent anti-oxidant properties once commonly used for the treatment of cardiovascular disease. Probucol therapy was found to stabilize cognitive symptoms in elderly AD patients, whereas in amyloid transgenic mice probucol was shown to attenuate amyloidosis. However, the mechanisms underlying the effects of probucol have note been determined. In the present study we investigated whether probucol can prevent BBB disturbances induced by chronic ingestion of proinflammatory diets enriched with either 20% (w/w) saturated fats (SFA) or 1% (w/w) cholesterol. Mice were fed the diets for 12 weeks before they were killed and BBB integrity was measured. Mice maintained on either the SFA- or cholesterol-supplemented diets were found to have a 30- and sevenfold greater likelihood of BBB dysfunction, respectively, as determined by the parenchymal extravasation of plasma-derived immunoglobulins and endogenous lipoprotein enrichment with β-amyloid. In contrast, mice fed the SFA- or cholesterol-enriched diets that also contained 1% (w/w) probucol showed no evidence of BBB disturbance. The parenchymal expression of glial fibrillary acidic protein, a marker of cerebrovascular inflammation, was significantly greater in mice fed the SFA-enriched diet. Plasma lipid, β-amyloid and apolipoprotein B levels were not increased by feeding of the SFA- or cholesterol-enriched diets. However, mice fed the SFA- or cholesterol-enriched diets did exhibit increased plasma non-esterified fatty acid levels that were not reduced by probucol. The data suggest that probucol prevents disturbances of BBB induced by chronic ingestion of diets enriched in SFA or cholesterol by suppressing inflammatory pathways rather than by modulating plasma lipid homeostasis. SN - 1440-1681 UR - https://www.unboundmedicine.com/medline/citation/23167559/Probucol_prevents_blood_brain_barrier_dysfunction_in_wild_type_mice_induced_by_saturated_fat_or_cholesterol_feeding_ L2 - https://doi.org/10.1111/1440-1681.12032 DB - PRIME DP - Unbound Medicine ER -