title: Carbamoyl-PROXYL-enhanced MRI detects very small disruptions in brain vascular permeability induced by dietary cholesterol.
abstract: BACKGROUND
  Gd-DTPA-enhanced magnetic resonance imaging (MRI) is a conventional method for non-invasive investigation of blood-brain-barrier (BBB) permeability in animal models. It allows the visualization of serious injury to the BBB. We developed a novel approach for detecting very small disruptions in BBB permeability induced by dietary cholesterol by using carbamoyl-PROXYL (CMP) as an MRI contrast probe.
  
  
  METHODS
  Mice were separated into two groups: normal diet (ND-mice) and high cholesterol diet (CD-mice). MRI-signal dynamics, plasma cholesterol, matrix metalloproteinase (MMP-9, MMP-2), and the white blood cell profile were analyzed. For the MRI analysis, two regions-of-interest (ROI) were selected: brain (ROI-1) and surrounding area (ROI-2).
  
  
  RESULTS
  In the ROI-2 of ND-mice, CMP- or Gd-enhanced MRI-signal followed typical kinetics with a half-life of signal decay (τ(1/2)) approximately 8 or approximately 15 min, respectively. In CD-mice, the MRI-signal increased continuously without decay. In the ROI-1 of ND- and CD-mice, MRI-signal enhancement was not detected by Gd-DTPA. In the ROI-1 of ND-mice, CMP-induced MRI-signal enhancement was negligible, while in CD-mice, it was significant (τ(1/2)>15 min). Hypercholesterolemia increased the plasma levels of MMP-9 and neutrophils.
  
  
  CONCLUSIONS
  Hypercholesterolemia increases vascular permeability, which is mediated by MMP-9 and neutrophils.
  
  
  CONCLUSIONS
  Even very small disruptions in brain vascular permeability could be detected by CMP-enhanced MRI but not by Gd-DTPA-enhanced MRI.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Itsuko
authors.initials: I
authors.lastname: Ishii
authors.forename: Zhivko
authors.initials: Z
authors.lastname: Zhelev
authors.forename: Ichio
authors.initials: I
authors.lastname: Aoki
authors.forename: Sayaka
authors.initials: S
authors.lastname: Shibata
authors.forename: Mitsukazu
authors.initials: M
authors.lastname: Kitada
authors.forename: Rumiana
authors.initials: R
authors.lastname: Bakalova
mesh_terms: D000818:Animals; D001835:Body Weight; D002199:Capillary Permeability / Q000187:drug effects*; D002560:Cerebrovascular Circulation; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice
chemical_list: D002791:Cholesterol, Dietary; D002784:Cholesterol