title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Public Health, Curtin University, Kent Street, Bentley, 6102, Western Australia. J.Mamo@curtin.edu.au
authors.forename: Menuka
authors.initials: M
authors.lastname: Pallebage-Gamarallage
authors.forename: Virginie
authors.initials: V
authors.lastname: Lam
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takechi
authors.forename: Susan
authors.initials: S
authors.lastname: Galloway
authors.forename: Karin
authors.initials: K
authors.lastname: Clark
authors.forename: John
authors.initials: J
authors.lastname: Mamo
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D000069059:Atorvastatin; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007052:Ibuprofen / Q000494:pharmacology; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001055:Apolipoproteins B; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D007074:Immunoglobulin G; D011758:Pyrroles; D000069059:Atorvastatin; D017035:Pravastatin; D007052:Ibuprofen