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Restoration of dietary-fat induced blood-brain barrier dysfunction by anti-inflammatory lipid-modulating agents.

Abstract

BACKGROUND

Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. Cerebrovascular disturbances are common pathological feature of Alzheimer's disease. We previously reported chronic ingestion of saturated fatty acids (SFA) compromises blood-brain barrier (BBB) integrity resulting in cerebral extravasation of plasma proteins and inflammation. However, the SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Restoration of BBB dysfunction is clinically relevant, so the purpose of this study was to explore lipid-lowering agents could reverse BBB disturbances induced by chronic ingestion of SFA's.

METHODS

Wild-type mice were fed an SFA diet for 12 weeks to induce BBB dysfunction, and then randomised to receive atorvastatin, pravastatin or ibuprofen in combination with the SFA-rich diet for 2 or 8 weeks. Abundance of plasma-derived immunoglobulin-G (IgG) and amyloid-β enriched apolipoprotein (apo)-B lipoproteins within brain parenchyme were quantified utilising immunofluorescence microscopy.

RESULTS

Atorvastatin treatment for 2 and 8 weeks restored BBB integrity, indicated by a substantial reduction of IgG and apo B, particularly within the hippocampus. Pravastatin, a water-soluble statin was less effective than atorvastatin (lipid-soluble). Statin effects were independent of changes in plasma lipid homeostasis. Ibuprofen, a lipid-soluble cyclooxygenase inhibitor attenuated cerebral accumulation of IgG and apo B as effectively as atorvastatin. Our findings are consistent with the drug effects being independent of plasma lipid homeostasis.

CONCLUSION

Our findings suggest that BBB dysfunction induced by chronic ingestion of SFA is reversible with timely introduction and sustained treatment with agents that suppress inflammation.

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  • Authors+Show Affiliations

    ,

    School of Public Health, Curtin University, Kent Street, Bentley, 6102, Western Australia. J.Mamo@curtin.edu.au

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    Source

    Lipids in health and disease 11: 2012 Sep 17 pg 117

    MeSH

    Amyloid beta-Peptides
    Animals
    Anti-Inflammatory Agents, Non-Steroidal
    Apolipoproteins B
    Atorvastatin
    Blood-Brain Barrier
    Brain
    Diet, High-Fat
    Female
    Heptanoic Acids
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Hypolipidemic Agents
    Ibuprofen
    Immunoglobulin G
    Mice
    Mice, Inbred C57BL
    Pravastatin
    Pyrroles

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22978403

    Citation

    Pallebage-Gamarallage, Menuka, et al. "Restoration of Dietary-fat Induced Blood-brain Barrier Dysfunction By Anti-inflammatory Lipid-modulating Agents." Lipids in Health and Disease, vol. 11, 2012, p. 117.
    Pallebage-Gamarallage M, Lam V, Takechi R, et al. Restoration of dietary-fat induced blood-brain barrier dysfunction by anti-inflammatory lipid-modulating agents. Lipids Health Dis. 2012;11:117.
    Pallebage-Gamarallage, M., Lam, V., Takechi, R., Galloway, S., Clark, K., & Mamo, J. (2012). Restoration of dietary-fat induced blood-brain barrier dysfunction by anti-inflammatory lipid-modulating agents. Lipids in Health and Disease, 11, p. 117. doi:10.1186/1476-511X-11-117.
    Pallebage-Gamarallage M, et al. Restoration of Dietary-fat Induced Blood-brain Barrier Dysfunction By Anti-inflammatory Lipid-modulating Agents. Lipids Health Dis. 2012 Sep 17;11:117. PubMed PMID: 22978403.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Restoration of dietary-fat induced blood-brain barrier dysfunction by anti-inflammatory lipid-modulating agents. AU - Pallebage-Gamarallage,Menuka, AU - Lam,Virginie, AU - Takechi,Ryusuke, AU - Galloway,Susan, AU - Clark,Karin, AU - Mamo,John, Y1 - 2012/09/17/ PY - 2012/07/23/received PY - 2012/09/05/accepted PY - 2012/9/18/entrez PY - 2012/9/18/pubmed PY - 2013/3/5/medline SP - 117 EP - 117 JF - Lipids in health and disease JO - Lipids Health Dis VL - 11 N2 - BACKGROUND: Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. Cerebrovascular disturbances are common pathological feature of Alzheimer's disease. We previously reported chronic ingestion of saturated fatty acids (SFA) compromises blood-brain barrier (BBB) integrity resulting in cerebral extravasation of plasma proteins and inflammation. However, the SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Restoration of BBB dysfunction is clinically relevant, so the purpose of this study was to explore lipid-lowering agents could reverse BBB disturbances induced by chronic ingestion of SFA's. METHODS: Wild-type mice were fed an SFA diet for 12 weeks to induce BBB dysfunction, and then randomised to receive atorvastatin, pravastatin or ibuprofen in combination with the SFA-rich diet for 2 or 8 weeks. Abundance of plasma-derived immunoglobulin-G (IgG) and amyloid-β enriched apolipoprotein (apo)-B lipoproteins within brain parenchyme were quantified utilising immunofluorescence microscopy. RESULTS: Atorvastatin treatment for 2 and 8 weeks restored BBB integrity, indicated by a substantial reduction of IgG and apo B, particularly within the hippocampus. Pravastatin, a water-soluble statin was less effective than atorvastatin (lipid-soluble). Statin effects were independent of changes in plasma lipid homeostasis. Ibuprofen, a lipid-soluble cyclooxygenase inhibitor attenuated cerebral accumulation of IgG and apo B as effectively as atorvastatin. Our findings are consistent with the drug effects being independent of plasma lipid homeostasis. CONCLUSION: Our findings suggest that BBB dysfunction induced by chronic ingestion of SFA is reversible with timely introduction and sustained treatment with agents that suppress inflammation. SN - 1476-511X UR - https://www.unboundmedicine.com/medline/citation/22978403/Restoration_of_dietary_fat_induced_blood_brain_barrier_dysfunction_by_anti_inflammatory_lipid_modulating_agents_ L2 - https://lipidworld.biomedcentral.com/articles/10.1186/1476-511X-11-117 DB - PRIME DP - Unbound Medicine ER -