BACKGROUND Research indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation. METHODS Mice with deficits of NOX2 organizer p47phox (p47phox-/-) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF. RESULTS Cognitive impairment induced by systemic inflammation was significantly attenuated in the p47phox-/- mice compared to that in the WT mice. The p47phox-/- mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47phox-/- mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection. CONCLUSIONS This study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation.

中文翻译：

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NADPH 氧化酶 2 作为保护小鼠全身炎症后认知缺陷的潜在治疗靶点

背景研究表明，败血症会增加发生认知障碍的风险。在全身性炎症后，大脑中会迅速诱导相应的小胶质细胞激活，并且还会释放多种神经毒性因子，包括炎症介质（例如，细胞因子）和活性氧（例如，超氧化物），从而导致神经元损伤。NADPH 氧化酶 (NOX) 酶通过产生超氧阴离子在小胶质细胞活化中发挥重要作用。我们假设 NOX 亚型，尤其是 NOX2，在发展由全身炎症引起的认知缺陷方面可能表现出非凡的能力。方法 本研究使用 NOX2 组织者 p47phox (p47phox-/-) 缺陷的小鼠和用 NOX 抑制剂二亚苯基碘 (DPI) 治疗的野生型 (WT) 小鼠。腹腔内脂多糖（LPS）注射用于诱导全身炎症。使用径向臂迷宫任务比较治疗组之间的空间学习和记忆。收集脑组织用于评估促炎细胞因子的转录水平，而进行免疫荧光染色和免疫印迹以确定活化神经胶质（小胶质细胞和星形胶质细胞）和受损神经元的百分比以及突触蛋白和 BDNF 的表达。结果 与 WT 小鼠相比，p47phox-/- 小鼠全身炎症引起的认知障碍显着减弱。p47phox-/- 小鼠表现出减少的小胶质细胞和星形胶质细胞活化和神经元损伤，并减弱了多种促炎细胞因子的诱导，包括肿瘤坏死因子-α、白细胞介素 (IL)-1β、IL-6 和 CCL2。与在 p47phox-/- 小鼠中观察到的类似，DPI 的给药显着减轻了认知障碍，降低了神经胶质激活和脑细胞因子浓度，并恢复了神经元和星形胶质细胞中突触后蛋白 (PSD-95) 和 BDNF 的表达，与注射 LPS 后 10 天内的载体处理对照相比。结论 本研究清楚地表明，在注射 LPS 的小鼠模型中，在全身炎症后，NOX2 有助于神经胶质激活，随后 BDNF 的表达降低、突触功能障碍和认知缺陷。我们的研究结果提供证据表明，NOX2 可能是一个有前景的药理学靶点，可用于预防全身炎症后的突触失调和认知障碍。