Neuroscience Letters | 2021
Blood-brain barrier permeability towards small and large tracers in a mouse model of osmotic demyelination syndrome
Abstract
During osmotic demyelination syndrome (ODS), myelin and oligodendrocyte are lost according to specific patterns in centro- or extra-pontine regions. In both experimental model of ODS and human cases, brain lesions are locally correlated with the disruption of the blood brain-barrier (BBB). The initiation, the degree and the duration of blood-brain barrier (BBB) opening as well as its contribution to brain damages are still a matter of debate. Using a panel of intravascular tracers from low- to high- molecular weight (from 0.45\u2009kDa 150\u2009kDa), we have assessed the BBB permeability at different timings of ODS induced experimentally in mice. ODS was mimicked according to a protocol of rapid correction of a chronic hyponatremia. We demonstrated that BBB leakage towards smallest tracers Lucifer Yellow (0.45\u2009kDa) and Texas Red-dextran (3\u2009kDa) was delayed by 36\u2009hours compared to the first clues of oligodendrocyte loss (occurring 12\u2009hours post-correction of hyponatremia). At 48\u2009hours post-correction and concomitantly to myelin loss, BBB was massively disrupted as attested by accumulation of Evans Blue (69\u2009kDa) and IgG (150\u2009kDa) in brain parenchyma. Analysis of BBB ultrastructure verified that brain endothelial cells had minimal alterations during chronic hyponatremia and at 12\u2009hours post-correction of hyponatremia. However, brain endothelium yielded worsened alterations at 48\u2009hours, such as enlarged vesicular to tubular-like cytoplasmic profiles of pinocytosis and/or transcytosis, local basal laminae abnormalities and sub-endothelial cavities. The protein expressions of occludin and claudin-1, involved in inter-endothelial tight junctions, were also downregulated at 48\u2009hours post-correction of hyponatremia. Our results revealed that functional BBB opening occured late in pre-established ODS lesions, and therefore was not a primary event initiating oligodendrocyte damages in the mouse model of ODS.