Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model

作者：Stefan A. Berghoff, Tim Düking, Lena Spieth, Jan Winchenbach, Sina K. Stumpf, Nina Gerndt, Kathrin Kusch, Torben Ruhwedel, Wiebke Möbius, Gesine Saher · 发表于：Acta Neuropathologica Communications · 年份：2017 · DOI：10.1186/s40478-017-0497-6 · 被引用次数：105 · 研究领域：Barrier Structure and Function Studies、Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments

In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.