Objective

Intracranial hemorrhage (ICH) catastrophically damages the cerebral vasculature, and severely compromises blood-brain barrier (BBB) function. The prognosis of ICH is poor due to the drastic and rapid progression of its pathology, and the lack of effective treatments presents a significant unmet clinical need. The present paper provides several evidences about the relationship between ICH bleeding status and mortality and the potential therapeutic effects of an iron chelator for ICH.

Methods

Zebrafish are a highly transparent animal model, allowing live imaging of the complex cerebral vasculature. Thus, to further elucidate ATV-induced ICH, we investigated the concentration- and time-dependent phenotypes of ATV-induced ICH with zebrafish larvae.

Results

The effects of ATV on mortality and ICH incidence in zebrafish larvae were concentration-dependent. Further, ATV treatment decreased vascular density of the hindbrain in a concentration-dependent manner, and hematoma volume was inversely correlated with ATV concentration. The number of cranial TUNEL-positive apoptotic cells was markedly increased 3 days post-fertilization. Importantly, the iron chelator deferasirox (DFR) decreased the incidence of ATV-induced ICH in zebrafish larvae.

Conclusion

These findings provided insight into the pathology and regulatory mechanism of ATV-induced ICH, and demonstrated the therapeutic effects of iron chelators.

中文翻译：

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铁螯合剂对阿托伐他汀引起的斑马鱼幼虫颅内出血的治疗作用

目的

颅内出血（ICH）灾难性地损害了脑血管，严重损害了血脑屏障（BBB）的功能。由于其病理学的急剧和迅速发展，ICH的预后很差，并且缺乏有效的治疗方法代表了严重的临床需求。本文提供了一些有关ICH出血状态与死亡率之间的关系的证据，以及铁螯合剂对ICH的潜在治疗作用。

方法

斑马鱼是高度透明的动物模型，可以对复杂的脑血管进行实时成像。因此，为进一步阐明ATV诱导的ICH，我们研究了斑马鱼幼虫对ATV诱导的ICH的浓度和时间依赖性表型。

结果

ATV对斑马鱼幼虫死亡率和ICH发病率的影响是浓度依赖性的。此外，ATV治疗以浓度依赖性方式降低后脑的血管密度，并且血肿体积与ATV浓度成反比。受精后3天颅TUNEL阳性凋亡细胞的数量明显增加。重要的是，铁螯合剂Deferasirox（DFR）降低了斑马鱼幼虫中ATV引起的ICH的发生率。

结论

这些发现提供了对ATV引起的ICH的病理学和调节机制的见解，并证明了铁螯合剂的治疗作用。