A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke
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DOI：
10.7150/thno.28252
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Bernaudin, Myriam
中科院分区：
文献类型：
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作者：
Khelif, Yacine;Toutain, Jerome;Bernaudin, Myriam
细胞外基质（ECM）的改变是缺血性中风后脑损伤发病机制中的主要事件之一。硫酸乙酰肝素模拟物 (HSm) 是合成的药理活性多糖，可促进各种类型病变中的 ECM 重塑和组织再生。 HSm 与生长因子结合，保护它们免受酶促降解并提高其生物利用度，从而促进组织修复。由于 ECM 在中风期间发生改变，并且 HSm 已被证明可以恢复 ECM，因此我们研究了 HSm4131（也称为 RGTA-4131 (R)）保护脑组织并促进中风后再生和可塑性的潜力。 方法：使用短暂（1 小时）管腔内大脑中动脉闭塞 (MCAo) 诱导大鼠缺血性中风。 MCAo 后不同时间（1、2.5 或 6 小时）将动物分配至治疗组（HSm4131；0.1、0.5、1.5 或 5 mg/kg）或载体对照组（盐水）。通过 MRI 评估闭塞后急性（2 天）和慢性（14 天）阶段的脑损伤。通过一系列感觉运动行为测试来评估功能缺陷。大脑中动脉再灌注后 5 分钟至 3 小时内分析了 HSm4131-Tc-99m 在缺血脑中的生物分布。通过免疫组织化学评估硫酸乙酰肝素的分布和细胞反应，包括血管生成和神经发生，并通过 RT-PCR 定量生长因子基因表达（VEGF-A、Ang-2）。 结果：在中风诱导后静脉注射 HSm4131，定位并保留在缺血半球中。 HSm4131 具有持久的神经保护作用，并在不改变生理参数的情况下显着减少功能缺陷。它还恢复了 ECM，并增加了受影响大脑半球的大脑可塑性过程，即血管生成和神经发生。结论：HSm 代表了一种有前途的基于 ECM 的治疗策略，可保护和修复中风后的大脑并有利于功能恢复。
Alteration of the extracellular matrix (ECM) is one of the major events in the pathogenesis of brain lesions following ischemic stroke. Heparan sulfate mimetics (HSm) are synthetic pharmacologically active polysaccharides that promote ECM remodeling and tissue regeneration in various types of lesions. HSm bind to growth factors, protect them from enzymatic degradation and increase their bioavailability, which promotes tissue repair. As the ECM is altered during stroke and HSm have been shown to restore the ECM, we investigated the potential of HSm4131 (also named RGTA-4131 (R)) to protect brain tissue and promote regeneration and plasticity after a stroke.Methods: Ischemic stroke was induced in rats using transient (1 h) intraluminal middle cerebral artery occlusion (MCAo). Animals were assigned to the treatment (HSm4131; 0.1, 0.5, 1.5, or 5 mg/kg) or vehicle control (saline) groups at different times (1, 2.5 or 6 h) after MCAo. Brain damage was assessed by MRI for the acute (2 days) and chronic (14 days) phases post-occlusion. Functional deficits were evaluated with a battery of sensorimotor behavioral tests. HSm4131-Tc-99m biodistribution in the ischemic brain was analyzed between 5 min and 3 h following middle cerebral artery reperfusion. Heparan sulfate distribution and cellular reactions, including angiogenesis and neurogenesis, were evaluated by immunohistochemistry, and growth factor gene expression (VEGF-A, Ang-2) was quantified by RT-PCR.Results: HSm4131, administered intravenously after stroke induction, located and remained in the ischemic hemisphere. HSm4131 conferred long-lasting neuroprotection, and significantly reduced functional deficits with no alteration of physiological parameters. It also restored the ECM, and increased brain plasticity processes, i.e., angiogenesis and neurogenesis, in the affected brain hemisphere.Conclusion: HSm represent a promising ECM-based therapeutic strategy to protect and repair the brain after a stroke and favor functional recovery.