Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
BioVisions, Inc., 9012 Wandering Trail Dr, Potomac, MD, 20854, USA.
Neuromolecular Med. 2018 Mar;20(1):63-72. doi: 10.1007/s12017-017-8474-6. Epub 2018 Jan 3.
Acute ischemic stroke causes a high rate of deaths and permanent neurological deficits in survivors. Current interventional treatment, in the form of enzymatic thrombolysis, benefits only a small percentage of patients. Brain ischemia triggers mobilization of innate immunity, specifically the complement system and Toll-like receptors (TLRs), ultimately leading to an exaggerated inflammatory response. Here we demonstrate that intravenous immunoglobulin (IVIG), a scavenger of potentially harmful complement fragments, and C1-esterase inhibitor (C1-INH), an inhibitor of complement activation, exert a beneficial effect on the outcome of experimental brain ischemia (I) and reperfusion (R) injury induced by transient occlusion of middle cerebral artery in mice. Both IVIG and C1-INH significantly and in a dose-responsive manner reduced brain infarction size, neurological deficit and mortality when administered to male mice 30 min before ischemia or up to 6 h after the onset of reperfusion. When combined, suboptimal doses of IVIG and C1-INH potentiated each other's neuroprotective therapeutic effects. Complement C3 and TLR2 signals were colocalized and significantly greater in brain cells adjacent to infracted brain lesions when compared to the corresponding regions of the contralateral hemisphere and to control (sham) mice. Treatment with IVIG and C1-INH effectively reduced deposition of C3b and downregulated excessive TLR2 and p-JNK1 expression at the site of I/R injury. Taken together, these results provide a rationale for potential use of IVIG and C1-INH, alone or in combination with ischemic stroke and other neurological conditions that involve inappropriately activated components of the innate immune system.
急性缺血性脑卒中导致幸存者死亡率和永久性神经功能缺损居高不下。目前的介入治疗方法（酶溶栓治疗）仅使一小部分患者受益。脑缺血引发固有免疫的动员，特别是补体系统和 Toll 样受体（TLRs），最终导致炎症反应过度。在这里，我们证明静脉注射免疫球蛋白（IVIG），一种潜在有害补体片段的清除剂，和 C1-酯酶抑制剂（C1-INH），一种补体激活抑制剂，对实验性脑缺血（I）和再灌注（R）损伤的结果具有有益作用，这种损伤是通过短暂性大脑中动脉闭塞在小鼠中诱导的。IVIG 和 C1-INH 在雄性小鼠缺血前 30 分钟或再灌注后 6 小时内给药时，均以剂量反应的方式显著减少脑梗死面积、神经功能缺损和死亡率。当 IVIG 和 C1-INH 的亚最佳剂量联合使用时，彼此的神经保护治疗效果增强。补体 C3 和 TLR2 信号在与对侧半球和对照（假手术）小鼠相应区域相比，在梗死病灶附近的脑细胞中发生共定位，并显著增加。用 IVIG 和 C1-INH 治疗可有效减少 C3b 的沉积，并下调 I/R 损伤部位过度的 TLR2 和 p-JNK1 表达。综上所述，这些结果为 IVIG 和 C1-INH 的潜在应用提供了依据，无论是单独使用还是与涉及固有免疫系统中不当激活成分的缺血性脑卒中及其他神经疾病联合使用。
