Tumor Necrosis Factor-α (TNF-α) is a proinflammatory cytokine implicated in neuronal damage in response to cerebral ischemia. Ischemic preconditioning (IPC) provides neuroprotection against a subsequent severer or longer transient ischemia by ischemic tolerance. Here, we focused on the role of TNF-α in IPC-mediated neuroprotection against neuronal death following a subsequent longer transient cerebral ischemia (TCI). Gerbils used in this study were randomly assigned to eight groups; sham group, TCI operated group, IPC plus (+) sham group, IPC + TCI operated group, sham + etanercept (an inhibitor of TNF-a) group, TCI + etanercept group, IPC + sham + etanercept group, and IPC + TCI + etanercept group. IPC was induced by a 2-min sublethal transient ischemia, which was operated 1 day prior to a longer (5-min) TCI. A significant death of neurons was found in the stratum pyramidale (SP) in the CA1 area (CA1) of the hippocampus 5 days after TCI; however, IPC protected SP neurons from TCI. We found that TNF-α immunoreactivity was significantly increased in CA1 pyramidal neurons in the TCI and IPC + TCI groups compared to the sham group. TNF-R1 expression in CA1 pyramidal neurons of the TCI group was also increased 1 and 2 days after TCI; however, in the IPC + TCI group, TNF-R1 expression was significantly lower than that in the TCI group. On the other hand, we did not detect TNF-R2 immunoreactivity in CA1 pyramidal neurons 1 and 2 days after TCI; meanwhile, in the IPC + TCI group, TNF-R2 expression was significantly increased compared to TNF-R2 expression at 1 and 2 days after TCI. In addition, in this group, TNF-R2 was newly expressed in pericytes, which are important cells in the blood brain barrier, from 1 day after TCI. When we treated etanercept to the IPC + TCI group, IPC-induced neuroprotection was significantly weakened. In brief, this study indicates that IPC confers neuroprotection against TCI by TNF-α signaling through TNF-R2 and suggests that the enhancement of TNF-R2 expression by IPC may be a legitimate strategy for a therapeutic intervention of TCI.

肿瘤坏死因子-α（TNF-α）是一种促炎细胞因子，与脑缺血反应有关，涉及神经元损伤。缺血预处理（IPC）通过缺血耐受性提供了针对随后的更严重或更长时间的短暂性缺血的神经保护作用。在这里，我们集中于TNF-α在随后更长的短暂性脑缺血（TCI）后IPC介导的神经元死亡的神经保护中的作用。这项研究中使用的沙鼠被随机分为8组。假手术组，TCI手术组，IPC加（+）假手术组，IPC + TCI手术组，假手术+依那西普（TNF-a抑制剂）组，TCI + etanercept组，IPC +假手术+依那西普组和IPC + TCI +依那西普组。IPC是由2分钟的致死性短暂性短暂脑缺血诱导的，该过程在更长（5分钟）的TCI之前1天进行。TCI后5天，在海马CA1区（CA1）的锥体层（SP）中发现了神经元的重大死亡；但是，IPC可以保护SP神经元免受TCI的侵害。我们发现，与假手术组相比，TCI和IPC + TCI组中CA1锥体神经元的TNF-α免疫反应性显着增加。在TCI后1天和2天，TCI组的CA1锥体神经元中的TNF-R1表达也增加了。然而，在IPC + TCI组中，TNF-R1的表达明显低于TCI组。另一方面，在TCI后1天和2天，我们未在CA1锥体神经元中检测到TNF-R2免疫反应。同时，在IPC + TCI组中，与TCI后1天和2天相比，TNF-R2的表达明显高于TNF-R2的表达。此外，在该组中，TNF-R2在周细胞中新表达，从TCI后1天起，它们是血脑屏障中的重要细胞。当我们将依那西普用于IPC + TCI组时，IPC诱导的神经保护作用显着减弱。简而言之，这项研究表明IPC通过TNF-R2通过TNF-α信号传导赋予TCI神经保护作用，并暗示IPC增强TNF-R2表达可能是治疗TCI的合法策略。