URPhyM - NARILIS, Université de Namur, Namur, Belgium; HEPH-Condorcet, Catégorie Paramédicale Charleroi, Charleroi, Belgium.
URPhyM - NARILIS, Université de Namur, Namur, Belgium.
Neurosci Lett. 2021 Feb 16;746:135665. doi: 10.1016/j.neulet.2021.135665. Epub 2021 Jan 23.
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 kDa 150 kDa), 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 kDa) and Texas Red-dextran (3 kDa) was delayed by 36 h compared to the first clues of oligodendrocyte loss (occurring 12 h post-correction of hyponatremia). At 48 h post-correction and concomitantly to myelin loss, BBB was massively disrupted as attested by accumulation of Evans Blue (69 kDa) and IgG (150 kDa) in brain parenchyma. Analysis of BBB ultrastructure verified that brain endothelial cells had minimal alterations during chronic hyponatremia and at 12 h post-correction of hyponatremia. However, brain endothelium yielded worsened alterations at 48 h, 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 h 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.
在渗透性脱髓鞘综合征（ODS）中，髓鞘和少突胶质细胞根据中枢或桥外区域的特定模式丢失。在 ODS 的实验模型和人类病例中，脑损伤与血脑屏障（BBB）的破坏有关。血脑屏障（BBB）的开启的起始、程度和持续时间及其对脑损伤的贡献仍存在争议。我们使用从小分子到高分子（0.45 kDa 到 150 kDa）的一系列血管内示踪剂，评估了实验诱导的小鼠 ODS 不同时间点的 BBB 通透性。ODS 是根据快速纠正慢性低钠血症的方案模拟的。我们证明，与少突胶质细胞丢失的第一个迹象（发生在低钠血症纠正后 12 小时）相比，BBB 对最小示踪剂 Lucifer Yellow（0.45 kDa）和 Texas Red-dextran（3 kDa）的渗漏延迟了 36 小时。在低钠血症纠正后 48 小时，伴随着髓鞘丢失，BBB 被大量破坏，脑实质中积累了 Evans Blue（69 kDa）和 IgG（150 kDa）。BBB 超微结构分析证实，在慢性低钠血症和低钠血症纠正后 12 小时，脑内皮细胞的改变最小。然而，在 48 小时时，脑内皮细胞的改变更为严重，如胞质内的内吞和/或转胞作用的泡状到管状样的细胞轮廓增大、局部基底膜异常和亚内皮腔。参与内皮细胞紧密连接的紧密连接蛋白 occludin 和 claudin-1 的蛋白表达也在低钠血症纠正后 48 小时下调。我们的结果表明，在预先建立的 ODS 病变中，功能性 BBB 开放发生较晚，因此不是引发 ODS 小鼠模型中少突胶质细胞损伤的初始事件。
