Sayeed Muhammad Shahdaat Bin, Alhadidi Qasim, Shah Zahoor A
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
J Neuroimmunol. 2017 Dec 15;313:46-55. doi: 10.1016/j.jneuroim.2017.10.007. Epub 2017 Oct 19.
Intracerebral hemorrhage (ICH) is the most severe form of stroke and is further exacerbated by the secondary injury involving inflammatory response due to the activation of microglia. This secondary injury is partly due to the toxic effects of hemin, an endogenous breakdown product of hemoglobin. Cofilin, an actin depolymerizing factor, controls actin dynamics and has been previously shown to be involved in mediating neuronal cell death in ischemic conditions and during bacterial lipopolysaccharide induced microglial activation. There are limited studies regarding the deleterious effects of extremely high concentrations of hemin released during ICH and its effects on microglia and subsequent cofilin response. Therefore, investigations were conducted to study the effects of hemin on microglial activation induced inflammation and the critical role of cofilin in mediating the response. We observed that hemin treated microglia had a concentration dependent increase in cofilin expression and NO production. There were increased levels of iNOS, TNF-α, HO1, Nrf2, Wfs-1, XBP-1 and spliced XBP-1 observed in response to hemin treatment and the signaling was found to be partly mediated by cofilin. Acute hemin treatment did not evoke Ca signaling and long-term treatment of hemin also resulted in the failure of microglial response to acetylcholine-evoked Ca signaling. Knockdown of cofilin by siRNA also reduced acetylcholine-evoked Ca signaling. These studies demonstrate that cofilin signaling is important in hemin-induced inflammation, oxidative stress, ER stress, microglial migration, and the ability to evoke Ca signaling. Therefore, cofilin inhibition could be a potential therapy in brain injuries triggered by hemin toxicity in conditions like ICH.
脑出血（ICH）是中风最严重的形式，由于小胶质细胞激活引发的炎症反应导致的继发性损伤会使其进一步恶化。这种继发性损伤部分归因于血红素的毒性作用，血红素是血红蛋白的内源性分解产物。丝切蛋白是一种肌动蛋白解聚因子，可控制肌动蛋白动力学，先前已证明其参与介导缺血条件下以及细菌脂多糖诱导的小胶质细胞激活过程中的神经元细胞死亡。关于脑出血期间释放的极高浓度血红素的有害影响及其对小胶质细胞和随后丝切蛋白反应的影响，相关研究有限。因此，开展了研究以探讨血红素对小胶质细胞激活诱导的炎症的影响以及丝切蛋白在介导该反应中的关键作用。我们观察到，用血红素处理的小胶质细胞中丝切蛋白表达和一氧化氮（NO）生成呈浓度依赖性增加。响应血红素处理，诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子-α（TNF-α）、血红素加氧酶-1（HO1）、核因子E2相关因子2（Nrf2）、沃尔夫勒姆综合征1（Wfs-1）、X盒结合蛋白1（XBP-1）和剪接型XBP-1的水平升高，且发现该信号传导部分由丝切蛋白介导。急性血红素处理未引发钙信号，长期血红素处理也导致小胶质细胞对乙酰胆碱诱发的钙信号反应失败。用小干扰RNA（siRNA）敲低丝切蛋白也降低了乙酰胆碱诱发的钙信号。这些研究表明，丝切蛋白信号传导在血红素诱导的炎症、氧化应激、内质网应激、小胶质细胞迁移以及诱发钙信号的能力中起重要作用。因此，抑制丝切蛋白可能是治疗脑出血等情况下由血红素毒性引发的脑损伤的一种潜在疗法。
