From the Université de Paris, NeuroDiderot, Inserm, Paris, France (C.C., M.A., C.D.L., A.-L.L., E.T.-L., G.B.).
Institute of Biochemistry and Biology, Potsdam University, Germany (C.O., S.A.-S.).
Stroke. 2020 Apr;51(4):1272-1278. doi: 10.1161/STROKEAHA.119.027207. Epub 2020 Jan 29.
Background and Purpose- Cerebral cavernous malformations (CCMs) are vascular malformations of the brain that lead to cerebral hemorrhages. A pharmacological treatment is needed especially for patients with nonoperable deep-seated lesions. We and others obtained CCM mouse models that were useful for mechanistic studies and rapid trials testing the preventive effects of candidate drugs. The shortened lifespan of acute mouse models hampered evaluation of compounds that would not only prevent lesion appearance but also cure preexisting lesions. Indirubin-3'-monoxime previously demonstrated its efficacy to reverse the cardiac phenotype of zebrafish mutants and to prevent lesion development in an acute CCM2 mouse model. In the present article, we developed and characterized a novel chronic CCM2 mouse model and evaluated the curative therapeutic effect of indirubin-3'-monoxime after CCM lesion development. Methods- The chronic mouse model was obtained by a postnatal induction of brain-endothelial-cell-specific ablation of the gene using the inducible -CreER mouse line. Results- We obtained a fully penetrant novel CCM chronic mouse model without any obvious off-target phenotypes and compatible with long-term survival. By 3 months of age, CCM lesions ranging in size from small isolated lesions to multiple caverns developed throughout the brain. Lesion burden was quantified in animals from 1 week to 5 months of age. Clear signs of intracerebral hemorrhages were noticed in brain-endothelial-cell-specific ablation of the gene. In contrast with its preventive effect in the acute CCM2 mouse model, a 20 mg/kg indirubin-3'-monoxime treatment for 3 weeks in 3-month old animals neither had any beneficial effect on the lesion burden nor alleviated cerebral hemorrhages. Conclusions- The brain-endothelial-cell-specific ablation of the gene chronic model is a strongly improved disease model for the CCM community whose challenge today is to decipher which candidate drugs might have a curative effect on patients' preexisting lesions. Visual Overview- An online visual overview is available for this article.
背景与目的-脑海绵状血管畸形（CCM）是脑内的血管畸形，可导致脑出血。对于无法手术的深部病变患者，需要进行药物治疗。我们和其他人获得了 CCM 小鼠模型，这些模型可用于机制研究和快速试验，以测试候选药物的预防效果。急性小鼠模型的寿命缩短，妨碍了评估不仅能预防病变出现，而且能治愈现有病变的化合物。靛玉红 3'-单肟先前已证明其能有效逆转斑马鱼突变体的心脏表型，并预防急性 CCM2 小鼠模型中的病变发展。在本文中，我们开发并表征了一种新型慢性 CCM2 小鼠模型，并评估了靛玉红 3'-单肟在 CCM 病变发展后的治疗效果。方法-通过使用诱导型 -CreER 小鼠系对脑内皮细胞特异性的基因进行出生后敲除，获得慢性小鼠模型。结果-我们获得了一种完全穿透的新型 CCM 慢性小鼠模型，没有任何明显的脱靶表型，并且能够长期存活。在 3 个月大时，大小从单个孤立病变到多个海绵状病变的 CCM 病变在整个大脑中发展。从 1 周龄到 5 月龄的动物中定量了病变负担。在基因特异性内皮细胞敲除的动物中，明显出现了颅内出血的迹象。与在急性 CCM2 小鼠模型中的预防作用相反，在 3 月龄的动物中，用 20mg/kg 的靛玉红 3'-单肟治疗 3 周，既没有对病变负担产生任何有益影响，也没有减轻脑出血。结论-基因特异性内皮细胞敲除的慢性模型是 CCM 领域的一个显著改进的疾病模型，目前的挑战是确定哪些候选药物可能对患者的现有病变具有治疗效果。可视化概述-本文提供了在线可视化概述。
