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Open Access Highly Accessed Research

Blood–brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

Angela E Schellenberg1*, Richard Buist2, Marc R Del Bigio3, Henrik Toft-Hansen45, Reza Khorooshi6, Trevor Owens67 and James Peeling12

Author Affiliations

1 Department of Pharmacology & Therapeutics, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada

2 Department of Radiology, University of Manitoba, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6, Canada

3 Department of Pathology, University of Manitoba, 715 McDermot Avenue, Winnipeg, Manitoba, R3E 3P4, Canada

4 Department of Clinical Immunology, Odense University Hospital, University of Southern Denmark, Sdr. Boulevard 29, 5000, Odense C, Denmark

5 Hans Christian Andersen Children’s Hospital, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

6 Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 25, 2. Sal, 5000, Odense C, Denmark

7 Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada

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Fluids and Barriers of the CNS 2012, 9:10  doi:10.1186/2045-8118-9-10

Published: 30 April 2012

Abstract

Background

The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, and which infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx).

Methods

This study used contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood–brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild-type mice. Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight junction protein.

Results

BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration and seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence of disruption in endothelial tight junctions was observed.

Conclusion

Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation.

Keywords:
Chemokine; Central nervous system; Inflammation; Multiple sclerosis; Magnetic resonance imaging