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

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.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.Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation.Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), wherein inflammation, demyelination, and blood–brain barrier (BBB) disruption occurs. The magnetic resonance imaging (MRI) contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA) does not move through the intact BBB. Following intravenous administration of Gd-DTPA, a signal increase on T1-weighted MR images is observed where the BBB is disrupted at sites of inflammation [1,2]. Histological studies using tracers [3-5] and contrast-enhanced MRI [6-9] have both shown that opening of the BBB is an early event in the development of the disease, though the exact mechanism that causes BBB disruption is currently unknown.The chemokine CCL2, previously known as monocyte chemoattractant protein-1, has a role in the recruitment of inflammatory cells into the CNS [10,11]. CCL2 is expressed within active and chronic MS lesions [11-14]. Astrocytes [13-15] and microglia [16] are believed to be sources of CCL2. Leukocytes accu