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 ccm2m201 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 Ccm2 gene using the inducible Slco1c1-CreERT2 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 Ccm2 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 Ccm2 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.

中文翻译：

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脑海绵状畸形的新型慢性小鼠模型。

背景和目的-脑海绵状畸形（CCM）是导致脑出血的大脑血管畸形。特别是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，这些模型可用于测试候选药物的预防作用的机理研究和快速试验。急性小鼠模型寿命的缩短阻碍了化合物的评估，这些化合物不仅可以预防病变的出现，而且可以治愈已有的病变。Indirubin-3'-monoxime先前在急性CCM2小鼠模型中证明了其逆转ccm2m201斑马鱼突变体的心脏表型和预防病变发展的功效。在本文中，我们开发并表征了一种新型的慢性CCM2小鼠模型，并评估了CCM病变发生后靛玉红3'-一肟的疗效。方法-慢性小鼠模型是使用可诱导的Slco1c1-CreERT2小鼠系通过产后诱导Ccm2基因对脑内皮细胞特异性消融获得的。结果-我们获得了一种完全渗透的新型CCM慢性小鼠模型，没有任何明显的脱靶表型，并且与长期生存相容。到3个月大时，CCM病变的大小不等，从孤立的小病变到整个脑部都有多个洞穴。在1周至5个月大的动物中定量病变负荷。Ccm2基因在脑内皮细胞特异性消融中发现了明显的脑出血迹象。与在急性CCM2小鼠模型中的预防作用相反，在3个月大的动物中进行20毫克/千克的靛玉红3'-一肟肟治疗3周，对病变负荷没有任何有益作用，也没有减轻脑出血。结论-Ccm2基因慢性模型的脑内皮细胞特异性消融是CCM社区的一种大大改善的疾病模型，其今天的挑战是确定哪种候选药物可能对患者先前存在的病变具有治愈作用。