Brain Advance Access published online on December 22, 2003
Brain, doi:10.1093/brain/awh068
© 2003 by Guarantors of Brain
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Article
1 Department of Molecular Cell Biology, VU Medical Centre, Amsterdam, The Netherlands
* Corresponding author. E-mail: he.devries{at}vumc.nl.
Received 24 July 2003
; revised 29 October 2003
; accepted 31 October 2003
Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.
Keywords: blood-brain barrier; monocytes; multiple sclerosis; lovastatin; MRI
Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis
2 Department of Experimental In Vivo NMR, Image Sciences Institute, University Medical Centre Utrecht, Utrecht, The Netherlands
3 Department of Biomedical Engineering, Section of Biomedical NMR, Eindhoven University of Technology, Eindhoven, The Netherlands
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Serres, D. C. Anthony, Y. Jiang, K. A. Broom, S. J. Campbell, D. J. Tyler, S. I. van Kasteren, B. G. Davis, and N. R. Sibson Systemic Inflammatory Response Reactivates Immune-Mediated Lesions in Rat Brain J. Neurosci., April 15, 2009; 29(15): 4820 - 4828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Fabis, T. W. Phares, R. B. Kean, H. Koprowski, and D. C. Hooper Blood-brain barrier changes and cell invasion differ between therapeutic immune clearance of neurotrophic virus and CNS autoimmunity PNAS, October 7, 2008; 105(40): 15511 - 15516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Chen, M. O. Breckwoldt, E. Aikawa, G. Chiang, and R. Weissleder Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis Brain, April 1, 2008; 131(4): 1123 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Vellinga, R. D. Oude Engberink, A. Seewann, P. J.W. Pouwels, M. P. Wattjes, S. M.A. van der Pol, C. Pering, C. H. Polman, H. E. de Vries, J. J.G. Geurts, et al. Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement Brain, March 1, 2008; 131(3): 800 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Oude Engberink, S. M. A. van der Pol, E. A. Dopp, H. E. de Vries, and E. L. A. Blezer Comparison of SPIO and USPIO for in Vitro Labeling of Human Monocytes: MR Detection and Cell Function Radiology, May 1, 2007; 243(2): 467 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jander, M. Schroeter, and A. Saleh Imaging Inflammation in Acute Brain Ischemia Stroke, February 1, 2007; 38(2): 642 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wiart, N. Davoust, J.-B. Pialat, V. Desestret, S. Moucharrafie, T.-H. Cho, M. Mutin, J.-B. Langlois, O. Beuf, J. Honnorat, et al. MRI Monitoring of Neuroinflammation in Mouse Focal Ischemia Stroke, January 1, 2007; 38(1): 131 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Reijerkerk, G. Kooij, S. M. A. van der Pol, S. Khazen, C. D. Dijkstra, and H. E. de Vries Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells FASEB J, December 1, 2006; 20(14): 2550 - 2552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Moore, N. Earl, R. Frenette, A. Styhler, J. A. Mancini, D. W. Nicholson, A. L. O. Hebb, T. Owens, and G. S. Robertson Peripheral Phosphodiesterase 4 Inhibition Produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) Prevents Experimental Autoimmune Encephalomyelitis J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 63 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Schreibelt, R. J. P. Musters, A. Reijerkerk, L. R. de Groot, S. M. A. van der Pol, E. M. L. Hendrikx, E. D. Dopp, C. D. Dijkstra, B. Drukarch, and H. E. de Vries Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity J. Immunol., August 15, 2006; 177(4): 2630 - 2637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kuhlmann, L. Remington, I. Cognet, L. Bourbonniere, S. Zehntner, F. Guilhot, A. Herman, A. Guay-Giroux, J. P. Antel, T. Owens, et al. Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis Am. J. Pathol., August 1, 2006; 169(2): 584 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Stoll and M. Bendszus Inflammation and Atherosclerosis: Novel Insights Into Plaque Formation and Destabilization Stroke, July 1, 2006; 37(7): 1923 - 1932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Dousset, B. Brochet, M.S.A. Deloire, L. Lagoarde, B. Barroso, J.-M. Caille, and K.G. Petry MR Imaging of Relapsing Multiple Sclerosis Patients Using Ultra-Small-Particle Iron Oxide and Compared with Gadolinium. AJNR Am. J. Neuroradiol., May 1, 2006; 27(5): 1000 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Manninger, L. L. Muldoon, G. Nesbit, T. Murillo, P. M. Jacobs, and E. A. Neuwelt An Exploratory Study of Ferumoxtran-10 Nanoparticles as a Blood-Brain Barrier Imaging Agent Targeting Phagocytic Cells in CNS Inflammatory Lesions AJNR Am. J. Neuroradiol., October 1, 2005; 26(9): 2290 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bendszus, A. Bartsch, and G. Stoll Is the disruption of the blood-brain barrier a prerequisite for cellular infiltration in autoimmune encephalitis? Brain, April 1, 2005; 128(4): E25 - E25. [Full Text] [PDF]
|
|
|
|
|
|
M. E. Gegg, R. Harry, D. Hankey, H. Zambarakji, G. Pryce, D. Baker, P. Adamson, V. Calder, and J. Greenwood Suppression of Autoimmune Retinal Disease by Lovastatin Does Not Require Th2 Cytokine Induction J. Immunol., February 15, 2005; 174(4): 2327 - 2335. [Abstract] [Full Text] [PDF]
|
|