Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA; Department of Pharmacy, Diyala Health Directorate, Ministry of Health, Iraq.
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Neuroscience. 2018 Jul 15;383:33-45. doi: 10.1016/j.neuroscience.2018.04.036. Epub 2018 May 8.
Intracerebral hemorrhage (ICH) resulting from the rupture of the blood vessels in the brain is associated with significantly higher mortality and morbidity. Clinical studies focused on alleviating the primary injury, hematoma formation and expansion, were largely ineffective, suggesting that secondary injury-induced inflammation and the formation of reactive species also contribute to the overall injury process. In this study, we explored the effects of cofilin knockdown in a mouse model of ICH. Animals given stereotaxic injections of cofilin siRNA, 72-h prior to induction of ICH by collagenase injection within the area of siRNA administration showed significantly decreased cofilin expression levels and lower hemorrhage volume and edema, and the animals performed significantly better in neurobehavioral tasks i.e., rotarod, grip strength and neurologic deficit scores. Cofilin siRNA knocked-down mice had reduced ICH-induced DNA fragmentation, blood-brain barrier disruption and microglial activation, with a concomitant increase in astrocyte activation. Increased expression of pro-survival proteins and decreased markers of oxidative stress were also observed in cofilin siRNA-treated mice possibly due to the reduced levels of cofilin. Our results suggest that cofilin plays a major role in ICH-induced secondary injury, and could become a potential therapeutic target.
脑出血（ICH）是由于大脑血管破裂引起的，与更高的死亡率和发病率相关。专注于减轻原发性损伤、血肿形成和扩大的临床研究基本上没有效果，这表明继发性损伤引起的炎症和活性物质的形成也会导致整体损伤过程。在这项研究中，我们探讨了在脑出血小鼠模型中下调丝切蛋白的作用。在胶原酶注射诱导脑出血前 72 小时，通过立体定向注射给予丝切蛋白 siRNA 的动物，其丝切蛋白表达水平显著降低，出血体积和水肿减少，并且在神经行为任务（如旋转棒、握力和神经缺陷评分）中表现明显更好。下调丝切蛋白的小鼠脑出血诱导的 DNA 片段化、血脑屏障破坏和小胶质细胞激活减少，同时星形胶质细胞激活增加。在丝切蛋白 siRNA 处理的小鼠中，还观察到促生存蛋白的表达增加和氧化应激标志物的减少，这可能是由于丝切蛋白水平降低所致。我们的结果表明，丝切蛋白在脑出血引起的继发性损伤中起主要作用，可能成为一个潜在的治疗靶点。
