Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Cell Mol Neurobiol. 2013 Apr;33(3):393-400. doi: 10.1007/s10571-013-9905-z. Epub 2013 Jan 16.
Acute encephalopathy is a generic term for acute brain dysfunction occurring after infection. Acute encephalopathy induced by influenza virus results in high mortality, and most cases of influenza-associated encephalopathy (IAE) result in brain edema. Administration of diclofenac sodium (DCF), a non-steroidal anti-inflammatory drug (NSAID), is associated with a significant increased mortality rate of IAE. These previous clinical findings proposed further investigation of DCF administration and brain edema to clarify how DCF aggravates IAE. Aquaporin-4 (AQP4) is the predominant water channel protein in the mammalian brain, and is mainly expressed in astrocytes. AQP4 plays an important role in brain water homeostasis. Therefore, we investigated a possible association between DCF and AQP4 production in astrocytes. We stimulated cultured rat astrocytes with three cytokines, interleukin-1β, tumor necrosis factor α, and interferon γ, and then treated with DCF. DCF enhanced proinflammatory cytokine-induced AQP4 gene and protein expression in astrocytes, whereas DCF alone did not change the AQP4 gene expression. The addition of nuclear factor-kappa B (NF-κB) inhibitor abrogated AQP4 gene and protein expression completely in astrocytes treated with cytokines alone and in those also treated with DCF. In conclusion, this study demonstrated that AQP4 is upregulated in astrocyte by proinflammatory cytokines, and that the addition of DCF further augments AQP4 production. This effect is mediated via NF-κB signaling. The enhancement of AQP4 production by DCF may explain the significantly increased mortality rates in IAE patients treated with DCF.
急性脑病是感染后发生的急性脑功能障碍的通用术语。流感病毒引起的急性脑病导致高死亡率，大多数流感相关脑病（IAE）导致脑水肿。非甾体抗炎药（NSAID）双氯芬酸钠（DCF）的给药与 IAE 的死亡率显著增加有关。这些先前的临床发现提出了进一步研究 DCF 给药和脑水肿的必要性，以阐明 DCF 如何加重 IAE。水通道蛋白-4（AQP4）是哺乳动物大脑中的主要水通道蛋白，主要在星形胶质细胞中表达。AQP4 在脑水稳态中发挥重要作用。因此，我们研究了 DCF 与星形胶质细胞中 AQP4 产生之间的可能关联。我们用三种细胞因子白细胞介素-1β、肿瘤坏死因子-α和干扰素-γ刺激培养的大鼠星形胶质细胞，然后用 DCF 处理。DCF 增强了促炎细胞因子诱导的星形胶质细胞中 AQP4 基因和蛋白的表达，而 DCF 本身不会改变 AQP4 基因的表达。核因子-κB（NF-κB）抑制剂的加入完全阻断了单独用细胞因子处理和也用 DCF 处理的星形胶质细胞中 AQP4 基因和蛋白的表达。总之，这项研究表明，促炎细胞因子可上调星形胶质细胞中的 AQP4，而 DCF 的加入进一步增强了 AQP4 的产生。这种作用是通过 NF-κB 信号转导介导的。DCF 增强 AQP4 的产生可能解释了接受 DCF 治疗的 IAE 患者死亡率显著增加的原因。
