Sorbonne Université, Inserm, CNRS, ICM-GH Pitié-Salpêtrière, F-75013 Paris, France.
AP-HP, Saint-Antoine Hospital, F-75012 Paris, France.
Brain. 2023 Jun 1;146(6):2453-2463. doi: 10.1093/brain/awad051.
In multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed. We have generated a Xenopus laevis transgenic model Tg(mbp:GFP-NTR) of conditional demyelination in which spontaneous remyelination can be accelerated using candidate molecules. Xenopus laevis is a classic model for in vivo studies of myelination because tadpoles are translucent. We reasoned that demyelination should translate into loss of sensorimotor functions followed by behavioural recovery upon remyelination. To this end, we measured the swimming speed and distance travelled before and after demyelination and during the ongoing spontaneous remyelination and have developed a functional assay based on the visual avoidance of a virtual collision. Here we show that alteration of these functional and clinical performances correlated well with the level of demyelination and that histological remyelination, assayed by counting in vivo the number of myelinating oligodendrocytes in the optic nerve, translated in clinical-functional recovery. This method was further validated in tadpoles treated with pro-remyelinating agents (clemastine, siponimod) showing that increased remyelination in the optic nerve was associated with functional improvement. Our data illustrate the potential interest of correlating histopathological parameters and functional-clinical parameters to screen molecules promoting remyelination in a simple in vivo model of conditional demyelination.
在多发性硬化症中，尽管在控制疾病的炎症成分方面取得了显著进展，但脱髓鞘病变的修复仍然是一个未满足的需求。尽管在实验模型中产生了令人鼓舞的结果，但一些有利于或促进髓鞘再生的候选药物在临床试验中并未达到预期结果。这些失败的一个可能原因是，在大多数情况下，在临床前测试中，仅通过组织学评估了疗效，而没有评估功能恢复。我们已经生成了一种条件性脱髓鞘的 Xenopus laevis 转基因模型 Tg(mbp:GFP-NTR)，可以使用候选分子加速自发性髓鞘再生。非洲爪蟾是髓鞘体内研究的经典模型，因为蝌蚪是半透明的。我们推断脱髓鞘应该导致感觉运动功能丧失，随后在髓鞘再生时出现行为恢复。为此，我们在脱髓鞘前后以及自发髓鞘再生过程中测量了游泳速度和游泳距离，并开发了一种基于虚拟碰撞视觉回避的功能测定法。在这里，我们表明，这些功能和临床性能的改变与脱髓鞘的程度密切相关，并且通过在视神经中计数体内髓鞘形成少突胶质细胞的数量来评估组织学髓鞘再生，与临床功能恢复相关。该方法在视神经中用促髓鞘再生剂（氯马斯汀、西尼莫德）处理的蝌蚪中得到进一步验证，表明视神经中髓鞘再生增加与功能改善相关。我们的数据说明了在简单的条件性脱髓鞘体内模型中，将组织病理学参数与功能临床参数相关联以筛选促进髓鞘再生的分子的潜在意义。
