Edaravone Administration Confers Neuroprotection after Experimental Intracerebral Hemorrhage in Rats via NLRP3 Suppression
Edaravone Administration Confers Neuroprotection after Experimental Intracerebral Hemorrhage in Rats via NLRP3 Suppression
复制标题
依达拉奉 (Edaravone) 通过抑制 NLRP3 为大鼠实验性脑出血后提供神经保护。
DOI：
10.1016/j.jstrokecerebrovasdis.2019.104468
复制
发表时间：
2020-01-01
影响因子：
2.5
通讯作者：
Tang, Jun
中科院分区：
文献类型：
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作者：
Miao, Hongping;Jiang, Yongxiang;Tang, Jun
目的：脑出血（Intracerebral hemorrhage，ICH）是导致成人致残和死亡的主要原因之一，目前尚无有效的治疗方法。依达拉奉在缺血性卒中后显示出其神经保护作用，但其在脑出血后的作用及其可能机制尚不清楚。在此，我们研究依达拉奉是否对大鼠脑出血后具有神经保护作用，并探讨其潜在机制。方法：立体定向注射自体血200 μ l，在SD大鼠右侧基底节区建立脑出血模型。依达拉奉（3 mg/kg）或溶剂（生理盐水）静脉给药，NLRP 3选择性拮抗剂（MCC 950，10 mg/kg）腹腔注射以研究潜在机制。采用Morris水迷宫试验和旋转棒试验观察脑出血后神经功能的变化，Fluoro-Jade C检测脑出血后神经元的变性。采用Western blot、RT-PCR和免疫组化方法检测细胞内相关分子的表达。结果：依达拉奉能明显减轻脑出血后大鼠的脑水肿，改善神经功能缺损。血肿增加了小胶质细胞中NLRP 3的表达，依达拉奉降低了NLRP 3的表达。此外，我们证明依达拉奉与MCC 950在减轻神经变性和降低IL-1 β、Caspase 1和NF-κ B在蛋白或mRNA中的表达方面具有相似的作用。依达拉奉和MCC 950均能增加血肿周围Tuj-1阳性神经细胞的数量。结论：本研究表明依达拉奉对脑出血后神经保护作用部分是通过抑制小胶质细胞NF-κ B依赖的NLRP 3发挥的，为依达拉奉在脑出血后的临床应用提供了新的证据。
Objectives: Intracerebral hemorrhage (ICH) is one of the leading causes of disability and mortality in adult, which lacks effective therapies. Edaravone has showed its neuroprotective effects after ischemia stroke, but its effects and possible mechanisms after ICH are poorly understood. Here, we investigated whether edaravone confers neuroprotection after ICH in rats and explored the potential mechanisms involved. Methods: ICH was induced in the right basal ganglia of Sprague-Dawley rats by stereotacticly injection of 200 mu l autologous blood. Edaravone (3 mg/kg) or vehicle (saline) was administered intravenously and NLRP3 selective antagonist (MCC950, 10 mg/kg) was intraperitoneally injected to study the potential mechanism. Water Morris Maze Test and Rotarod test were used to elucidate neurological function and Fluoro-Jade C was used to study neurodegeneration after ICH. Western blot assay, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to check the expression of molecules involved. Results: As a result, we found that edaravone significantly alleviated brain edema and conferred the neurological deficits of rats after ICH. Hematoma increased NLRP3 expression in microglia, which was decreased by edaravone. Moreover, we demonstrated that edaravone shared a similar effect with MCC950 on alleviating neurodegeneration and decreasing the expression of IL-1 beta, Caspase 1 and NF-kappa B in protein or mRNA. Lastly, edaravone and MCC950 both increased the number of Tuj-1 positive neuronal cells peripheral hematoma. Conclusions: The present study demonstrated that edaravone conducted neuroprotection after ICH partially via suppressing NF-kappa B-dependent NLRP3 in microglia, which contributed a novel evidence for clinic usage of edaravone after ICH.