Carbamoyl-PROXYL-enhanced MRI detects very small disruptions in brain vascular permeability induced by dietary cholesterol

• Published in: Biochimica et biophysica acta Vol. 1810; no. 12; pp. 1309 - 1316
• Main Authors: Tomizawa, Atsuyuki, Ishii, Itsuko, Zhelev, Zhivko, Aoki, Ichio, Shibata, Sayaka, Kitada, Mitsukazu, Bakalova, Rumiana
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2011
• Subjects: 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; Animals; Blood-brain barrier; Body Weight; Capillary Permeability - drug effects; Cerebrovascular Circulation; Cholesterol - blood; Cholesterol, Dietary - pharmacology; Hypercholesterolemia; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Matrix metalloproteinase; Mice; Neutrophils; MCAO; CD; BBB; MRI; Neutrophils; Gd-DTPA; Matrix metalloproteinase; ROI; MMP; ZO-1; Hypercholesterolemia; Blood-brain barrier; Magnetic resonance imaging; ND; CSF; 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl; carbamoyl-PROXYL; TIMP
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2011.06.011

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. 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). 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) ~ 8 or ~ 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. Hypercholesterolemia increases vascular permeability, which is mediated by MMP-9 and neutrophils. Even very small disruptions in brain vascular permeability could be detected by CMP-enhanced MRI but not by Gd-DTPA-enhanced MRI. ► Hypercholesterolemia-induced disruptions of vascular permeability in the brain. ► New MRI approach for detection of very small disruptions of vascular permeability. ► For this purpose, carbamoyl-PROXYL is most appropriate contrast probe than Gd. ► Dietary cholesterol increases the level of plasma matrix metalloproteinase-9. ► Dietary cholesterol increases the level of plasma neutrophils.